Nutrient chapter

Calcium

Nutritional calcium element; distinct from free Ca2+, salts, mineral deposits and calcium-signaling events. Nutritional element; not elemental metal exposure, free calcium ion, or a specific calcium salt. Forms and intake are recorded in each event.

119 recorded mechanisms · 32 availability situations · 1 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Extracellular calcium activates cloned bovine CaSR expressed in Xenopus oocytes.
Calcium ion → Calcium-sensing receptor / CaSR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Bovine parathyroid receptor cDNA; Xenopus oocyte expression
limitations
Heterologous expression; polyvalent ions also activate this receptor.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Bos taurus receptor in Xenopus laevis
plain_language
CaSR senses calcium outside cells.
primary_references
[brown1993] Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid (1993). https://pubmed.ncbi.nlm.nih.gov/8255296/ DOI: 10.1038/366575a0
tissue_or_cell_type
Parathyroid-derived receptor; plasma membrane
Calcium: mechanism-first literature curation (2026-09-17) · lines 14–23
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine parathyroid receptor cDNA; Xenopus oocyte expression · source_derived_draft · unverified_draft
### calcium-activates-casr Extracellular calcium activates cloned bovine CaSR expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: CaSR senses calcium outside cells. organism: Bos taurus receptor in Xenopus laevis tissue_or_cell_type: Parathyroid-derived receptor; plasma membrane experimental_model: Bovine parathyroid receptor cDNA; Xenopus oocyte expression limitations: Heterologous expression; polyvalent ions also activate this receptor. [brown1993] Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid (1993). https://pubmed.ncbi.nlm.nih.gov/8255296/ DOI: 10.1038/366575a0
Complete structured claim and evidence
CaSR potentiation by NPS R-568 strengthens extracellular-calcium-mediated inhibition of PTH secretion in bovine parathyroid cells.
Calcium-sensing receptor / CaSR → Parathyroid hormone secretion source_derived_draftungraded
Experimental context and source evidence
experimental_model
Bovine parathyroid cells and human CaSR-expressing HEK293 cells
limitations
Pharmacological cell experiment; potentiation required extracellular calcium.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Bos taurus
plain_language
Greater calcium-sensor activation reduces hormone release.
primary_references
[nemeth1998] Calcimimetics with potent and selective activity on the parathyroid calcium receptor (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19959/ DOI: 10.1073/pnas.95.7.4040
tissue_or_cell_type
Parathyroid cells
Calcium: mechanism-first literature curation (2026-09-17) · lines 25–34
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine parathyroid cells and human CaSR-expressing HEK293 cells · source_derived_draft · unverified_draft
### casr-calcium-pth-suppression CaSR potentiation by NPS R-568 strengthens extracellular-calcium-mediated inhibition of PTH secretion in bovine parathyroid cells. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Greater calcium-sensor activation reduces hormone release. organism: Bos taurus tissue_or_cell_type: Parathyroid cells experimental_model: Bovine parathyroid cells and human CaSR-expressing HEK293 cells limitations: Pharmacological cell experiment; potentiation required extracellular calcium. [nemeth1998] Calcimimetics with potent and selective activity on the parathyroid calcium receptor (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19959/ DOI: 10.1073/pnas.95.7.4040
Complete structured claim and evidence
Inactivating CASR variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism.
Calcium-sensing receptor / CaSR → Serum calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Human pedigrees and mutant-receptor expression in Xenopus oocytes
limitations
Mutation-specific inherited disease; not evidence of dietary calcium excess.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A faulty sensor can raise blood calcium.
primary_references
[pollak1993] Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (1993). https://pubmed.ncbi.nlm.nih.gov/7916660/ DOI: 10.1016/0092-8674(93)90617-y
tissue_or_cell_type
Parathyroid/kidney calcium regulation
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 36–45
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human pedigrees and mutant-receptor expression in Xenopus oocytes · source_derived_draft · unverified_draft
### casr-loss-hypercalcemia Inactivating CASR variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A faulty sensor can raise blood calcium. organism: Homo sapiens tissue_or_cell_type: Parathyroid/kidney calcium regulation experimental_model: Human pedigrees and mutant-receptor expression in Xenopus oocytes limitations: Mutation-specific inherited disease; not evidence of dietary calcium excess. [pollak1993] Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (1993). https://pubmed.ncbi.nlm.nih.gov/7916660/ DOI: 10.1016/0092-8674(93)90617-y
Complete structured claim and evidence
The CaSR E128A variant increases receptor responsiveness and causes dominant hypocalcemia in the studied family.
Calcium-sensing receptor / CaSR → Serum calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Human family; E128A CaSR expressed in Xenopus oocytes
limitations
One family and oocyte assays; not dietary calcium deficiency.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
An oversensitive sensor can lower blood calcium.
primary_references
[pollak1994] Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation (1994). https://pubmed.ncbi.nlm.nih.gov/7874174/ DOI: 10.1038/ng1194-303
tissue_or_cell_type
Systemic calcium regulation
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 47–56
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family; E128A CaSR expressed in Xenopus oocytes · source_derived_draft · unverified_draft
### casr-gain-hypocalcemia The CaSR E128A variant increases receptor responsiveness and causes dominant hypocalcemia in the studied family. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An oversensitive sensor can lower blood calcium. organism: Homo sapiens tissue_or_cell_type: Systemic calcium regulation experimental_model: Human family; E128A CaSR expressed in Xenopus oocytes limitations: One family and oocyte assays; not dietary calcium deficiency. [pollak1994] Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation (1994). https://pubmed.ncbi.nlm.nih.gov/7874174/ DOI: 10.1038/ng1194-303
Complete structured claim and evidence
PTH increases TRPV5 activity through cAMP-PKA-dependent phosphorylation at T709 in receptor/channel expression assays.
Parathyroid hormone / PTH → TRPV5 source_derived_draftungraded
Experimental context and source evidence
experimental_model
HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis
limitations
Response required strong intracellular calcium buffering; cultured-cell mechanism.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Heterologous HEK293 expression system
plain_language
PTH can increase calcium entry through TRPV5.
primary_references
[degroot2009] Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2723979/ DOI: 10.1681/ASN.2008080873
tissue_or_cell_type
Plasma membrane; distal-nephron mechanism
Calcium: mechanism-first literature curation (2026-09-17) · lines 58–67
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis · source_derived_draft · unverified_draft
### pth-activates-trpv5 PTH increases TRPV5 activity through cAMP-PKA-dependent phosphorylation at T709 in receptor/channel expression assays. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PTH can increase calcium entry through TRPV5. organism: Heterologous HEK293 expression system tissue_or_cell_type: Plasma membrane; distal-nephron mechanism experimental_model: HEK293 expression, calcium uptake, FRET, patch clamp and TRPV5 mutagenesis limitations: Response required strong intracellular calcium buffering; cultured-cell mechanism. [degroot2009] Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation (2009). https://pmc.ncbi.nlm.nih.gov/articles/PMC2723979/ DOI: 10.1681/ASN.2008080873
Complete structured claim and evidence
Thyroparathyroidectomy nearly abolished calcitriol production in low-calcium-fed rats; parathyroid extract restored it.
Parathyroid hormone / PTH → Calcitriol production source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Low-calcium-fed rats; thyroparathyroidectomy and parathyroid-extract replacement
limitations
Surgical removal plus extract replacement; not a purified-enzyme assay.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus
plain_language
Hormonal support helps activate vitamin D during calcium restriction.
primary_references
[garabedian1972] Control of 25-hydroxycholecalciferol metabolism by parathyroid glands (1972). https://pubmed.ncbi.nlm.nih.gov/4340153/ DOI: 10.1073/pnas.69.7.1673
tissue_or_cell_type
Systemic vitamin D metabolism
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 69–78
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Low-calcium-fed rats; thyroparathyroidectomy and parathyroid-extract replacement · source_derived_draft · unverified_draft
### parathyroid-loss-calcitriol-production Thyroparathyroidectomy nearly abolished calcitriol production in low-calcium-fed rats; parathyroid extract restored it. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Hormonal support helps activate vitamin D during calcium restriction. organism: Rattus norvegicus tissue_or_cell_type: Systemic vitamin D metabolism experimental_model: Low-calcium-fed rats; thyroparathyroidectomy and parathyroid-extract replacement limitations: Surgical removal plus extract replacement; not a purified-enzyme assay. [garabedian1972] Control of 25-hydroxycholecalciferol metabolism by parathyroid glands (1972). https://pubmed.ncbi.nlm.nih.gov/4340153/ DOI: 10.1073/pnas.69.7.1673
Complete structured claim and evidence
Calcitriol administration suppresses parathyroid PTH transcription in rats without a measured rise in serum calcium.
Calcitriol → Parathyroid hormone gene transcription source_derived_draftungraded
Experimental context and source evidence
experimental_model
Vitamin D metabolite administration to rats; parathyroid RNA and nuclear transcription assays
limitations
Administered hormone and transcription assay; does not resolve every promoter mechanism.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus
plain_language
Active vitamin D feeds back on hormone production.
primary_references
[silver1986] Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat (1986). https://pubmed.ncbi.nlm.nih.gov/3771798/ DOI: 10.1172/JCI112714
tissue_or_cell_type
Parathyroid
Calcium: mechanism-first literature curation (2026-09-17) · lines 80–89
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Vitamin D metabolite administration to rats; parathyroid RNA and nuclear transcription assays · source_derived_draft · unverified_draft
### calcitriol-suppresses-pth-transcription Calcitriol administration suppresses parathyroid PTH transcription in rats without a measured rise in serum calcium. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Active vitamin D feeds back on hormone production. organism: Rattus norvegicus tissue_or_cell_type: Parathyroid experimental_model: Vitamin D metabolite administration to rats; parathyroid RNA and nuclear transcription assays limitations: Administered hormone and transcription assay; does not resolve every promoter mechanism. [silver1986] Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat (1986). https://pubmed.ncbi.nlm.nih.gov/3771798/ DOI: 10.1172/JCI112714
Complete structured claim and evidence
Recombinant FGF23 lowers renal CYP27B1 mRNA before the fall in serum phosphate.
Fibroblast growth factor 23 / FGF23 → Vitamin D 1-alpha-hydroxylase / CYP27B1 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant FGF23 injections in normal and parathyroidectomized rodents
limitations
Injection study; transcript change is not direct enzyme inhibition.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus; Rattus norvegicus
plain_language
FGF23 restrains a vitamin D activation enzyme.
primary_references
[shimada2004injection] FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis (2004). https://pubmed.ncbi.nlm.nih.gov/15040831/ DOI: 10.1359/JBMR.0301264
tissue_or_cell_type
Kidney
Calcium: mechanism-first literature curation (2026-09-17) · lines 91–100
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant FGF23 injections in normal and parathyroidectomized rodents · source_derived_draft · unverified_draft
### fgf23-reduces-cyp27b1-expression Recombinant FGF23 lowers renal CYP27B1 mRNA before the fall in serum phosphate. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: FGF23 restrains a vitamin D activation enzyme. organism: Mus musculus; Rattus norvegicus tissue_or_cell_type: Kidney experimental_model: Recombinant FGF23 injections in normal and parathyroidectomized rodents limitations: Injection study; transcript change is not direct enzyme inhibition. [shimada2004injection] FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis (2004). https://pubmed.ncbi.nlm.nih.gov/15040831/ DOI: 10.1359/JBMR.0301264
Complete structured claim and evidence
Recombinant FGF23 raises renal CYP24A1 mRNA as circulating calcitriol declines.
Fibroblast growth factor 23 / FGF23 → Vitamin D 24-hydroxylase / CYP24A1 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant FGF23 injections in normal and parathyroidectomized rodents
limitations
Acute rodent transcript response; does not quantify human calcium balance.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus; Rattus norvegicus
plain_language
FGF23 increases vitamin D inactivation machinery.
primary_references
[shimada2004injection] FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis (2004). https://pubmed.ncbi.nlm.nih.gov/15040831/ DOI: 10.1359/JBMR.0301264
tissue_or_cell_type
Kidney
Calcium: mechanism-first literature curation (2026-09-17) · lines 102–111
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant FGF23 injections in normal and parathyroidectomized rodents · source_derived_draft · unverified_draft
### fgf23-increases-cyp24a1-expression Recombinant FGF23 raises renal CYP24A1 mRNA as circulating calcitriol declines. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: FGF23 increases vitamin D inactivation machinery. organism: Mus musculus; Rattus norvegicus tissue_or_cell_type: Kidney experimental_model: Recombinant FGF23 injections in normal and parathyroidectomized rodents limitations: Acute rodent transcript response; does not quantify human calcium balance. [shimada2004injection] FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis (2004). https://pubmed.ncbi.nlm.nih.gov/15040831/ DOI: 10.1359/JBMR.0301264
Complete structured claim and evidence
Alpha-Klotho cooperates with FGFR1(IIIc) to confer high-affinity binding and signaling by FGF23.
Alpha-Klotho / KL → Fibroblast growth factor receptor 1 / FGFR1 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Renal homogenates, receptor-reconstitution cell assays and anti-Klotho antibody in mice
limitations
Specifically FGFR1(IIIc) reconstitution; not all FGFR1 splice forms are equivalent.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mammalian cell systems; Mus musculus
plain_language
FGF23 needs a suitable receptor partnership.
primary_references
[urakawa2006] Klotho converts canonical FGF receptor into a specific receptor for FGF23 (2006). https://pubmed.ncbi.nlm.nih.gov/17086194/ DOI: 10.1038/nature05315
tissue_or_cell_type
Kidney receptor system
Calcium: mechanism-first literature curation (2026-09-17) · lines 113–122
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Renal homogenates, receptor-reconstitution cell assays and anti-Klotho antibody in mice · source_derived_draft · unverified_draft
### klotho-fgfr1-fgf23-receptor Alpha-Klotho cooperates with FGFR1(IIIc) to confer high-affinity binding and signaling by FGF23. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: FGF23 needs a suitable receptor partnership. organism: Mammalian cell systems; Mus musculus tissue_or_cell_type: Kidney receptor system experimental_model: Renal homogenates, receptor-reconstitution cell assays and anti-Klotho antibody in mice limitations: Specifically FGFR1(IIIc) reconstitution; not all FGFR1 splice forms are equivalent. [urakawa2006] Klotho converts canonical FGF receptor into a specific receptor for FGF23 (2006). https://pubmed.ncbi.nlm.nih.gov/17086194/ DOI: 10.1038/nature05315
Complete structured claim and evidence
FGF23 increases renal distal-tubular TRPV5 membrane abundance through FGFR/alpha-Klotho signaling involving ERK1/2, SGK1 and WNK4.
Fibroblast growth factor 23 / FGF23 → TRPV5 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices
limitations
Mouse genetic/pharmacological models; no claim of equivalent human effect magnitude.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
FGF23 can help kidneys retain calcium.
primary_references
[andrukhova2014] FGF23 promotes renal calcium reabsorption through the TRPV5 channel (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3983685/ DOI: 10.1002/embj.201284188
tissue_or_cell_type
Renal distal tubules
Calcium: mechanism-first literature curation (2026-09-17) · lines 124–133
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices · source_derived_draft · unverified_draft
### fgf23-increases-trpv5-membrane-abundance FGF23 increases renal distal-tubular TRPV5 membrane abundance through FGFR/alpha-Klotho signaling involving ERK1/2, SGK1 and WNK4. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: FGF23 can help kidneys retain calcium. organism: Mus musculus tissue_or_cell_type: Renal distal tubules experimental_model: Mouse Fgf23/Klotho/Vdr genetic models, recombinant FGF23, isolated tubules and kidney slices limitations: Mouse genetic/pharmacological models; no claim of equivalent human effect magnitude. [andrukhova2014] FGF23 promotes renal calcium reabsorption through the TRPV5 channel (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC3983685/ DOI: 10.1002/embj.201284188
Complete structured claim and evidence
VDR-ablated mice develop hypocalcemia around postnatal day 21 with rising PTH.
Vitamin D receptor / VDR → Serum calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Mice with targeted disruption of the VDR DNA-binding domain
limitations
Global receptor deletion; not isolated dietary calcium shortage.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Vitamin D receptor failure disrupts calcium regulation.
primary_references
[li1997] Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC23277/ DOI: 10.1073/pnas.94.18.9831
tissue_or_cell_type
Systemic mineral metabolism
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 135–144
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mice with targeted disruption of the VDR DNA-binding domain · source_derived_draft · unverified_draft
### vdr-loss-hypocalcemia VDR-ablated mice develop hypocalcemia around postnatal day 21 with rising PTH. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin D receptor failure disrupts calcium regulation. organism: Mus musculus tissue_or_cell_type: Systemic mineral metabolism experimental_model: Mice with targeted disruption of the VDR DNA-binding domain limitations: Global receptor deletion; not isolated dietary calcium shortage. [li1997] Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia (1997). https://pmc.ncbi.nlm.nih.gov/articles/PMC23277/ DOI: 10.1073/pnas.94.18.9831
Complete structured claim and evidence
A mineral/lactose rescue diet normalizes ionized calcium in VDR-ablated mice.
Calcium → Serum ionized calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
VDR-ablated mice and controls fed a mineral/lactose rescue diet
limitations
Combined dietary intervention; cannot attribute rescue to calcium alone.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Dietary mineral delivery can bypass part of receptor failure.
primary_references
[li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262
reported_effect
normalizing
tissue_or_cell_type
Intestine and blood
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 146–156
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · VDR-ablated mice and controls fed a mineral/lactose rescue diet · source_derived_draft · unverified_draft
### vdr-null-mineral-diet-rescue A mineral/lactose rescue diet normalizes ionized calcium in VDR-ablated mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Dietary mineral delivery can bypass part of receptor failure. organism: Mus musculus tissue_or_cell_type: Intestine and blood experimental_model: VDR-ablated mice and controls fed a mineral/lactose rescue diet limitations: Combined dietary intervention; cannot attribute rescue to calcium alone. reported_effect: normalizing [li1998] Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice (1998). https://pubmed.ncbi.nlm.nih.gov/9751523/ DOI: 10.1210/endo.139.10.6262
Complete structured claim and evidence
Trpv6 deletion reduced intestinal calcium absorption by about 60% in the Bianco mouse model.
TRPV6 → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Whole-body Trpv6 knockout mice under regular and low-calcium diets
limitations
Whole-body deletion; diet and assay matter; residual absorption remained.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
TRPV6 materially supports calcium uptake in this model.
primary_references
[bianco2007] Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene (2007). https://pubmed.ncbi.nlm.nih.gov/17129178/ DOI: 10.1359/jbmr.061110
tissue_or_cell_type
Intestine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 158–167
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Whole-body Trpv6 knockout mice under regular and low-calcium diets · source_derived_draft · unverified_draft
### trpv6-loss-reduces-absorption Trpv6 deletion reduced intestinal calcium absorption by about 60% in the Bianco mouse model. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV6 materially supports calcium uptake in this model. organism: Mus musculus tissue_or_cell_type: Intestine experimental_model: Whole-body Trpv6 knockout mice under regular and low-calcium diets limitations: Whole-body deletion; diet and assay matter; residual absorption remained. [bianco2007] Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene (2007). https://pubmed.ncbi.nlm.nih.gov/17129178/ DOI: 10.1359/jbmr.061110
Complete structured claim and evidence
Significant active duodenal calcium transport persists in Trpv6/calbindin-D9k double-null mice under the tested stimulation conditions.
TRPV6 and calbindin-D9k → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays
limitations
Residual transport does not establish dispensability under every diet or life stage.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Other routes can support active calcium absorption.
primary_references
[benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2408805/ DOI: 10.1210/en.2007-1655
reported_effect
retained
tissue_or_cell_type
Duodenum
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 169–179
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays · source_derived_draft · unverified_draft
### trpv6-calbindin-independent-active-transport Significant active duodenal calcium transport persists in Trpv6/calbindin-D9k double-null mice under the tested stimulation conditions. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Other routes can support active calcium absorption. organism: Mus musculus tissue_or_cell_type: Duodenum experimental_model: Trpv6 and calbindin-D9k single/double knockout mice; duodenal transport assays limitations: Residual transport does not establish dispensability under every diet or life stage. reported_effect: retained [benn2008] Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2408805/ DOI: 10.1210/en.2007-1655
Complete structured claim and evidence
Calcitriol induces human TRPV6 transcription through VDR/RXR-associated regulatory elements in intestinal cell models.
Calcitriol → TRPV6 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human intestinal cell lines; chromatin immunoprecipitation, promoter reporters and regulatory-element mutagenesis
limitations
Promoter activity and receptor occupancy do not establish an exclusive transport route or whole-body calcium flux.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens cell lines
plain_language
Active vitamin D increases a calcium-entry channel.
primary_references
[meyer2006] The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells (2006). https://pubmed.ncbi.nlm.nih.gov/16574738/ DOI: 10.1210/me.2006-0031
tissue_or_cell_type
Intestinal cell transcriptional regulation
Calcium: mechanism-first literature curation (2026-09-17) · lines 181–190
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human intestinal cell lines; chromatin immunoprecipitation, promoter reporters and regulatory-element mutagenesis · source_derived_draft · unverified_draft
### calcitriol-vdr-induces-trpv6 Calcitriol induces human TRPV6 transcription through VDR/RXR-associated regulatory elements in intestinal cell models. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Active vitamin D increases a calcium-entry channel. organism: Homo sapiens cell lines tissue_or_cell_type: Intestinal cell transcriptional regulation experimental_model: Human intestinal cell lines; chromatin immunoprecipitation, promoter reporters and regulatory-element mutagenesis limitations: Promoter activity and receptor occupancy do not establish an exclusive transport route or whole-body calcium flux. [meyer2006] The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells (2006). https://pubmed.ncbi.nlm.nih.gov/16574738/ DOI: 10.1210/me.2006-0031
Complete structured claim and evidence
Claudin-2 manipulation changes calcium permeability across Caco-2 epithelial monolayers.
Claudin-2 → Paracellular calcium permeability source_derived_draftungraded
Experimental context and source evidence
experimental_model
Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression
limitations
Cell-line permeability; not an obligatory route in every intestinal segment.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens cell line
plain_language
Claudin-2 supports calcium movement between cells.
primary_references
[fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973
tissue_or_cell_type
Caco-2 epithelial tight junctions
Calcium: mechanism-first literature curation (2026-09-17) · lines 192–201
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression · source_derived_draft · unverified_draft
### cldn2-calcium-permeability Claudin-2 manipulation changes calcium permeability across Caco-2 epithelial monolayers. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Claudin-2 supports calcium movement between cells. organism: Homo sapiens cell line tissue_or_cell_type: Caco-2 epithelial tight junctions experimental_model: Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression limitations: Cell-line permeability; not an obligatory route in every intestinal segment. [fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973
Complete structured claim and evidence
Claudin-12 knockdown/overexpression alters calcium permeability in Caco-2 monolayers.
Claudin-12 → Paracellular calcium permeability source_derived_draftungraded
Experimental context and source evidence
experimental_model
Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression
limitations
Assay context matters; this does not prove a mandatory claudin-2/12 complex.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens cell line
plain_language
Claudin-12 contributes another between-cell route.
primary_references
[fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973
tissue_or_cell_type
Caco-2 epithelial tight junctions
Calcium: mechanism-first literature curation (2026-09-17) · lines 203–212
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression · source_derived_draft · unverified_draft
### cldn12-calcium-permeability Claudin-12 knockdown/overexpression alters calcium permeability in Caco-2 monolayers. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Claudin-12 contributes another between-cell route. organism: Homo sapiens cell line tissue_or_cell_type: Caco-2 epithelial tight junctions experimental_model: Caco-2 knockdown/overexpression and mouse VDR-null intestinal expression limitations: Assay context matters; this does not prove a mandatory claudin-2/12 complex. [fujita2008] Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2366872/ DOI: 10.1091/mbc.E07-09-0973
Complete structured claim and evidence
Cldn2/Cldn12 double deletion lowers colonic calcium permeability; small-intestinal permeability was unchanged.
Claudin-2 and claudin-12 → Colonic paracellular calcium permeability source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models
limitations
Global double knockout; single proteins are partly redundant.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
The measured defect was segment specific.
primary_references
[beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118
tissue_or_cell_type
Colon
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 214–223
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models · source_derived_draft · unverified_draft
### cldn2-cldn12-double-loss-colon Cldn2/Cldn12 double deletion lowers colonic calcium permeability; small-intestinal permeability was unchanged. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The measured defect was segment specific. organism: Mus musculus tissue_or_cell_type: Colon experimental_model: Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models limitations: Global double knockout; single proteins are partly redundant. [beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118
Complete structured claim and evidence
Cldn2/Cldn12 double-null mice lose more urinary calcium than Cldn2-null mice.
Claudin-2 and claudin-12 → Urinary calcium excretion source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models
limitations
Global deletion also affects intestinal handling.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
The two claudins provide complementary renal retention.
primary_references
[beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118
tissue_or_cell_type
Kidney; proximal-tubule localization
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 225–234
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models · source_derived_draft · unverified_draft
### cldn2-cldn12-double-loss-calciuria Cldn2/Cldn12 double-null mice lose more urinary calcium than Cldn2-null mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two claudins provide complementary renal retention. organism: Mus musculus tissue_or_cell_type: Kidney; proximal-tubule localization experimental_model: Cldn2/Cldn12 single/double knockout mice, ex vivo epithelia and cell models limitations: Global deletion also affects intestinal handling. [beggs2021] Claudin-2 and claudin-12 form independent, complementary pores required to maintain calcium homeostasis (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8694054/ DOI: 10.1073/pnas.2111247118
Complete structured claim and evidence
Trpv5-null mice have impaired distal calcium reabsorption and severe hypercalciuria despite increased vitamin D levels.
TRPV5 → Renal calcium reabsorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays
limitations
Mouse knockout with micropuncture localization.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Hormonal compensation cannot replace the missing channel.
primary_references
[hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826
tissue_or_cell_type
Early distal convolution
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 236–245
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays · source_derived_draft · unverified_draft
### trpv5-loss-renal-reabsorption Trpv5-null mice have impaired distal calcium reabsorption and severe hypercalciuria despite increased vitamin D levels. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Hormonal compensation cannot replace the missing channel. organism: Mus musculus tissue_or_cell_type: Early distal convolution experimental_model: Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays limitations: Mouse knockout with micropuncture localization. [hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826
Complete structured claim and evidence
Trpv5-null mice show increased intestinal absorption of orally administered calcium tracer.
TRPV5 → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays
limitations
Compensation accompanies renal loss; not direct intestinal TRPV5 transport.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Gut uptake compensates for kidney losses.
primary_references
[hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826
tissue_or_cell_type
Intestine
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 247–256
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays · source_derived_draft · unverified_draft
### trpv5-loss-compensatory-intestinal-absorption Trpv5-null mice show increased intestinal absorption of orally administered calcium tracer. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Gut uptake compensates for kidney losses. organism: Mus musculus tissue_or_cell_type: Intestine experimental_model: Trpv5 knockout mice; renal micropuncture and oral calcium tracer assays limitations: Compensation accompanies renal loss; not direct intestinal TRPV5 transport. [hoenderop2003] Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 (2003). https://pmc.ncbi.nlm.nih.gov/articles/PMC297001/ DOI: 10.1172/JCI19826
Complete structured claim and evidence
Claudin-16/19 coexpression increases paracellular cation selectivity in LLC-PK1 epithelial monolayers.
Claudin-16 → Claudin-19 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Claudin expression in LLC-PK1/MDCK epithelia; interaction and permeability assays
limitations
Effects differ in MDCK cells; cation selectivity does not prove a calcium-specific pore.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Heterologous renal epithelial systems
plain_language
These renal junction proteins work together.
primary_references
[hou2008] Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2176193/ DOI: 10.1172/JCI33970
tissue_or_cell_type
Renal tight-junction model
Calcium: mechanism-first literature curation (2026-09-17) · lines 258–267
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Claudin expression in LLC-PK1/MDCK epithelia; interaction and permeability assays · source_derived_draft · unverified_draft
### cldn16-cldn19-cation-selectivity Claudin-16/19 coexpression increases paracellular cation selectivity in LLC-PK1 epithelial monolayers. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: These renal junction proteins work together. organism: Heterologous renal epithelial systems tissue_or_cell_type: Renal tight-junction model experimental_model: Claudin expression in LLC-PK1/MDCK epithelia; interaction and permeability assays limitations: Effects differ in MDCK cells; cation selectivity does not prove a calcium-specific pore. [hou2008] Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2176193/ DOI: 10.1172/JCI33970
Complete structured claim and evidence
Biallelic CLDN19 variants were identified in families with renal magnesium wasting, hypercalciuria and nephrocalcinosis.
Claudin-19 → Urinary calcium excretion source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Human affected families; linkage, sequencing and claudin trafficking/assembly assays
limitations
Multimineral genetic disorder; ocular and renal manifestations vary.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Inherited junction defects can waste calcium.
primary_references
[konrad2006] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pmc.ncbi.nlm.nih.gov/articles/PMC1698561/ DOI: 10.1086/508617
tissue_or_cell_type
Kidney tubules
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 269–278
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human affected families; linkage, sequencing and claudin trafficking/assembly assays · source_derived_draft · unverified_draft
### cldn19-variants-renal-calcium-wasting Biallelic CLDN19 variants were identified in families with renal magnesium wasting, hypercalciuria and nephrocalcinosis. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inherited junction defects can waste calcium. organism: Homo sapiens tissue_or_cell_type: Kidney tubules experimental_model: Human affected families; linkage, sequencing and claudin trafficking/assembly assays limitations: Multimineral genetic disorder; ocular and renal manifestations vary. [konrad2006] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement (2006). https://pmc.ncbi.nlm.nih.gov/articles/PMC1698561/ DOI: 10.1086/508617
Complete structured claim and evidence
Intestinal Atp2b1 deletion prevented the active-calcium-transport increase elicited by calcitriol in control mice.
Plasma membrane calcium ATPase 1 / ATP2B1 → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Villin-Cre intestine-specific Atp2b1 deletion in mice
limitations
Conditional deletion and administered calcitriol; basal absorption was not shown to be zero.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
A calcium pump is needed for this hormone response.
primary_references
[ryan2015] Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3 (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4772868/ DOI: 10.1016/j.bbrc.2015.09.087
tissue_or_cell_type
Intestinal absorptive cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 280–289
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Villin-Cre intestine-specific Atp2b1 deletion in mice · source_derived_draft · unverified_draft
### intestinal-pmca1-loss-calcitriol-response Intestinal Atp2b1 deletion prevented the active-calcium-transport increase elicited by calcitriol in control mice. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium pump is needed for this hormone response. organism: Mus musculus tissue_or_cell_type: Intestinal absorptive cells experimental_model: Villin-Cre intestine-specific Atp2b1 deletion in mice limitations: Conditional deletion and administered calcitriol; basal absorption was not shown to be zero. [ryan2015] Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3 (2015). https://pmc.ncbi.nlm.nih.gov/articles/PMC4772868/ DOI: 10.1016/j.bbrc.2015.09.087
Complete structured claim and evidence
Reducing calcium intake from 2000 to 300 mg/day increased intact PTH within one week in nine healthy women.
Calcium → Serum PTH concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention
limitations
Small controlled study; low intake is not proof of symptomatic deficiency.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Low intake recruits a hormonal response.
primary_references
[dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62
tissue_or_cell_type
Blood
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 291–300
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention · source_derived_draft · unverified_draft
### low-calcium-intake-increases-pth Reducing calcium intake from 2000 to 300 mg/day increased intact PTH within one week in nine healthy women. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low intake recruits a hormonal response. organism: Homo sapiens tissue_or_cell_type: Blood experimental_model: Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention limitations: Small controlled study; low intake is not proof of symptomatic deficiency. [dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62
Complete structured claim and evidence
The same diet reduction increased fractional oral 47Ca retention within one week.
Calcium → Fractional whole-body calcium retention source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention
limitations
Retention indexes absorption; greater fraction does not guarantee adequate absolute uptake.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The retained fraction adapts to low intake.
primary_references
[dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62
tissue_or_cell_type
Whole body
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 302–311
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention · source_derived_draft · unverified_draft
### low-calcium-intake-fractional-retention The same diet reduction increased fractional oral 47Ca retention within one week. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The retained fraction adapts to low intake. organism: Homo sapiens tissue_or_cell_type: Whole body experimental_model: Nine healthy women; controlled 2000-to-300 mg/day calcium diet change and oral 47Ca retention limitations: Retention indexes absorption; greater fraction does not guarantee adequate absolute uptake. [dawsonhughes1988] Effect of lowering dietary calcium intake on fractional whole body calcium retention (1988). https://pubmed.ncbi.nlm.nih.gov/3132484/ DOI: 10.1210/jcem-67-1-62
Complete structured claim and evidence
In 691 patients with stage 3-5 CKD, total calcium showed only fair agreement with ionized-calcium classification.
Serum total calcium concentration → Serum ionized calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
691 patients with stage 3-5 chronic kidney disease; paired calcium measurements
limitations
CKD cohort; albumin correction did not improve prediction.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Total and ionized calcium are different measurements.
primary_references
[gauci2008] Pitfalls of measuring total blood calcium in patients with CKD (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2488254/ DOI: 10.1681/ASN.2007040449
research_relationship_category
biomarker
tissue_or_cell_type
Blood
trigger_kind
biomarker_context Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 313–323
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 691 patients with stage 3-5 chronic kidney disease; paired calcium measurements · source_derived_draft · unverified_draft
### total-calcium-imperfect-ionized-proxy-ckd In 691 patients with stage 3-5 CKD, total calcium showed only fair agreement with ionized-calcium classification. Condition category: biomarker_context nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Total and ionized calcium are different measurements. organism: Homo sapiens tissue_or_cell_type: Blood experimental_model: 691 patients with stage 3-5 chronic kidney disease; paired calcium measurements limitations: CKD cohort; albumin correction did not improve prediction. research_relationship_category: biomarker [gauci2008] Pitfalls of measuring total blood calcium in patients with CKD (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2488254/ DOI: 10.1681/ASN.2007040449
Complete structured claim and evidence
Common albumin-adjusted calcium formulas generally classified ionized calcium no better than unadjusted total calcium in a 22,658-adult comparison.
Albumin-adjusted total calcium estimate → Serum ionized calcium concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Cross-sectional comparison of paired laboratory tests in 22,658 adults in Alberta
limitations
Cross-sectional tested population; formulas and patient context differ.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calculated correction is not a direct ionized-calcium test.
primary_references
[desgagnes2025] Use of Albumin-Adjusted Calcium Measurements in Clinical Practice (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC11751745/ DOI: 10.1001/jamanetworkopen.2024.55251
research_relationship_category
biomarker
tissue_or_cell_type
Blood
trigger_kind
biomarker_context Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 325–335
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional comparison of paired laboratory tests in 22,658 adults in Alberta · source_derived_draft · unverified_draft
### albumin-adjustment-calcium-misclassification Common albumin-adjusted calcium formulas generally classified ionized calcium no better than unadjusted total calcium in a 22,658-adult comparison. Condition category: biomarker_context nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calculated correction is not a direct ionized-calcium test. organism: Homo sapiens tissue_or_cell_type: Blood experimental_model: Cross-sectional comparison of paired laboratory tests in 22,658 adults in Alberta limitations: Cross-sectional tested population; formulas and patient context differ. research_relationship_category: biomarker [desgagnes2025] Use of Albumin-Adjusted Calcium Measurements in Clinical Practice (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC11751745/ DOI: 10.1001/jamanetworkopen.2024.55251
Complete structured claim and evidence
Mice with intestinal Vdr deletion maintained serum calcium despite calcium malabsorption and impaired skeletal mineral storage.
Serum calcium concentration → Calcium nutritional status source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice
limitations
Growing-mouse genetic model; not a validated human dietary diagnostic.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Normal blood calcium can coexist with inadequate skeletal supply.
primary_references
[lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3336970/ DOI: 10.1172/JCI45890
research_relationship_category
biomarker
tissue_or_cell_type
Blood, intestine and skeleton
trigger_kind
biomarker_context Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 337–347
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice · source_derived_draft · unverified_draft
### normal-serum-calcium-does-not-establish-sufficiency Mice with intestinal Vdr deletion maintained serum calcium despite calcium malabsorption and impaired skeletal mineral storage. Condition category: biomarker_context nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Normal blood calcium can coexist with inadequate skeletal supply. organism: Mus musculus tissue_or_cell_type: Blood, intestine and skeleton experimental_model: Intestinal and osteoblast Vdr deletion, low-calcium diets, and skeletal assays in growing mice limitations: Growing-mouse genetic model; not a validated human dietary diagnostic. research_relationship_category: biomarker [lieben2012] Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC3336970/ DOI: 10.1172/JCI45890
Complete structured claim and evidence
Recombinant human CYP27B1 converts calcifediol to calcitriol by 1-alpha-hydroxylation in reconstituted enzyme systems.
Vitamin D 1-alpha-hydroxylase / CYP27B1 → Calcitriol source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human CYP27B1 expressed in bacteria and reconstituted with phospholipids and electron-transfer partners
limitations
Activity requires electron-transfer support; this assay does not measure endocrine flux in an intact kidney.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens enzyme
plain_language
CYP27B1 activates the vitamin D precursor.
primary_references
[tang2012cyp27b1] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles (2012). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08736.x DOI: 10.1111/j.1742-4658.2012.08736.x
research_relationship_category
biochemical_reaction
tissue_or_cell_type
Reconstituted membrane system
transport_or_reaction_direction
forward
Calcium: mechanism-first literature curation (2026-09-17) · lines 349–360
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human CYP27B1 expressed in bacteria and reconstituted with phospholipids and electron-transfer partners · source_derived_draft · unverified_draft
### cyp27b1-produces-calcitriol Recombinant human CYP27B1 converts calcifediol to calcitriol by 1-alpha-hydroxylation in reconstituted enzyme systems. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP27B1 activates the vitamin D precursor. organism: Homo sapiens enzyme tissue_or_cell_type: Reconstituted membrane system experimental_model: Recombinant human CYP27B1 expressed in bacteria and reconstituted with phospholipids and electron-transfer partners limitations: Activity requires electron-transfer support; this assay does not measure endocrine flux in an intact kidney. research_relationship_category: biochemical_reaction transport_or_reaction_direction: forward [tang2012cyp27b1] Expression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles (2012). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08736.x DOI: 10.1111/j.1742-4658.2012.08736.x
Complete structured claim and evidence
Human CYP24A1 hydroxylates calcitriol to 1-alpha,24,25-trihydroxyvitamin D3 in the first C24-oxidation step.
Vitamin D 24-hydroxylase / CYP24A1 → 1-alpha,24,25-Trihydroxyvitamin D3 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human CYP24A1 expressed in E. coli, partially purified and reconstituted in phospholipid vesicles
limitations
This is a C24-pathway intermediate, not a final inactive product. Further oxidation and the distinct C23 route are not represented by this single edge.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens enzyme
plain_language
CYP24A1 begins a defined calcitriol breakdown route.
primary_references
[tieu2014] Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway (2014). https://pubmed.ncbi.nlm.nih.gov/24893882/ DOI: 10.1111/febs.12862
research_relationship_category
biochemical_reaction
tissue_or_cell_type
Reconstituted enzyme/membrane system
transport_or_reaction_direction
forward
Calcium: mechanism-first literature curation (2026-09-17) · lines 362–373
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human CYP24A1 expressed in E. coli, partially purified and reconstituted in phospholipid vesicles · source_derived_draft · unverified_draft
### cyp24a1-calcitriol-c24-hydroxylation Human CYP24A1 hydroxylates calcitriol to 1-alpha,24,25-trihydroxyvitamin D3 in the first C24-oxidation step. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: CYP24A1 begins a defined calcitriol breakdown route. organism: Homo sapiens enzyme tissue_or_cell_type: Reconstituted enzyme/membrane system experimental_model: Human CYP24A1 expressed in E. coli, partially purified and reconstituted in phospholipid vesicles limitations: This is a C24-pathway intermediate, not a final inactive product. Further oxidation and the distinct C23 route are not represented by this single edge. research_relationship_category: biochemical_reaction transport_or_reaction_direction: forward [tieu2014] Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway (2014). https://pubmed.ncbi.nlm.nih.gov/24893882/ DOI: 10.1111/febs.12862
Complete structured claim and evidence
Cloned rabbit ECaC, now termed TRPV5, confers calcium influx when expressed in Xenopus oocytes.
TRPV5 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
experimental_model
Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes
limitations
Expression assay; epithelial localization supports an apical role but does not quantify all renal calcium transport.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Oryctolagus cuniculus channel in Xenopus laevis
plain_language
TRPV5 provides a calcium entry channel.
primary_references
[hoenderop1999] Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia (1999). https://pubmed.ncbi.nlm.nih.gov/10085067/ DOI: 10.1074/jbc.274.13.8375
tissue_or_cell_type
Plasma membrane; renal epithelial channel origin
transport_effect
raises Confers calcium influx when expressed.
transport_or_reaction_direction
inward
transport_pool
cytosolic calcium Confers calcium influx when expressed.
Calcium: mechanism-first literature curation (2026-09-17) · lines 375–385
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes · source_derived_draft · unverified_draft
### trpv5-direct-calcium-permeation Cloned rabbit ECaC, now termed TRPV5, confers calcium influx when expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV5 provides a calcium entry channel. organism: Oryctolagus cuniculus channel in Xenopus laevis tissue_or_cell_type: Plasma membrane; renal epithelial channel origin experimental_model: Rabbit ECaC/TRPV5 cloning, epithelial localization and expression in Xenopus oocytes limitations: Expression assay; epithelial localization supports an apical role but does not quantify all renal calcium transport. transport_or_reaction_direction: inward [hoenderop1999] Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia (1999). https://pubmed.ncbi.nlm.nih.gov/10085067/ DOI: 10.1074/jbc.274.13.8375
Complete structured claim and evidence
Rat CaT1, now termed TRPV6, mediates electrogenic calcium uptake when expressed in Xenopus oocytes.
TRPV6 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
experimental_model
Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology
limitations
Heterologous uptake is not proof that every intestinal calcium ion uses this channel.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus channel in Xenopus laevis
plain_language
TRPV6 permits calcium entry across a membrane.
primary_references
[peng1999] Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption (1999). https://pubmed.ncbi.nlm.nih.gov/10428857/ DOI: 10.1074/jbc.274.32.22739
tissue_or_cell_type
Plasma membrane; duodenal channel origin
transport_effect
raises Mediates electrogenic calcium uptake when expressed.
transport_or_reaction_direction
inward
transport_pool
cytosolic calcium Mediates electrogenic calcium uptake when expressed.
Calcium: mechanism-first literature curation (2026-09-17) · lines 387–397
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology · source_derived_draft · unverified_draft
### trpv6-direct-calcium-permeation Rat CaT1, now termed TRPV6, mediates electrogenic calcium uptake when expressed in Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TRPV6 permits calcium entry across a membrane. organism: Rattus norvegicus channel in Xenopus laevis tissue_or_cell_type: Plasma membrane; duodenal channel origin experimental_model: Rat duodenal CaT1/TRPV6 expression in Xenopus oocytes; uptake and electrophysiology limitations: Heterologous uptake is not proof that every intestinal calcium ion uses this channel. transport_or_reaction_direction: inward [peng1999] Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption (1999). https://pubmed.ncbi.nlm.nih.gov/10428857/ DOI: 10.1074/jbc.274.32.22739
Complete structured claim and evidence
Calcium-loaded calmodulin forms the Ca2+/CaM regulatory complex resolved with a myosin-light-chain-kinase target peptide.
Calcium ion → Calmodulin source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic protein complex
experimental_model
Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography
limitations
Structure of a peptide complex; not a measurement of dietary calcium effects or every calmodulin target.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Purified vertebrate proteins
plain_language
Calmodulin carries bound calcium while engaging a target protein.
primary_references
[ca-meador1992] Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex (1992). https://pubmed.ncbi.nlm.nih.gov/1519061/ DOI: 10.1126/science.1519061
research_relationship_category
binding
tissue_or_cell_type
Smooth-muscle target-peptide system
Calcium: mechanism-first literature curation (2026-09-17) · lines 399–410
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography · source_derived_draft · unverified_draft
### ca-calmodulin-calcium-complex Calcium-loaded calmodulin forms the Ca2+/CaM regulatory complex resolved with a myosin-light-chain-kinase target peptide. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calmodulin carries bound calcium while engaging a target protein. organism: Purified vertebrate proteins tissue_or_cell_type: Smooth-muscle target-peptide system experimental_model: Purified calcium-bound calmodulin and a chicken smooth-muscle myosin light-chain kinase peptide; crystallography limitations: Structure of a peptide complex; not a measurement of dietary calcium effects or every calmodulin target. research_relationship_category: binding compartment_description: Cytosolic protein complex [ca-meador1992] Target enzyme recognition by calmodulin: 2.4 A structure of a calmodulin-peptide complex (1992). https://pubmed.ncbi.nlm.nih.gov/1519061/ DOI: 10.1126/science.1519061
Complete structured claim and evidence
Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition.
Calcium/calmodulin → Calcineurin source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol
experimental_model
Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry
limitations
Fragment and biochemical data support a regulatory mechanism; not tissue-level output.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calcium-bound calmodulin helps switch on calcineurin.
primary_references
[ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008
research_relationship_category
regulation
tissue_or_cell_type
Recombinant signaling proteins
Calcium: mechanism-first literature curation (2026-09-17) · lines 412–423
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry · source_derived_draft · unverified_draft
### ca-calmodulin-calcineurin-activation Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin helps switch on calcineurin. organism: Homo sapiens tissue_or_cell_type: Recombinant signaling proteins experimental_model: Recombinant human alpha-calcineurin, regulatory fragments and calmodulin; spectroscopy and exchange mass spectrometry limitations: Fragment and biochemical data support a regulatory mechanism; not tissue-level output. research_relationship_category: regulation compartment_description: Cytosol [ca-rumimasante2012] Structural basis for activation of calcineurin by calmodulin (2012). https://pubmed.ncbi.nlm.nih.gov/22100452/ DOI: 10.1016/j.jmb.2011.11.008
Complete structured claim and evidence
Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation.
Calcineurin → NFAT1 / NFATC2 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol and nucleus
experimental_model
Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays
limitations
NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Calcineurin connects calcium signaling to NFAT1 activation.
primary_references
[ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884
research_relationship_category
regulation
tissue_or_cell_type
T lymphocytes
Calcium: mechanism-first literature curation (2026-09-17) · lines 425–436
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays · source_derived_draft · unverified_draft
### ca-calcineurin-nfat1-regulation Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcineurin connects calcium signaling to NFAT1 activation. organism: Mus musculus tissue_or_cell_type: T lymphocytes experimental_model: Murine T-cell experiments, inhibitor/chelation interventions and protein-binding assays limitations: NFAT1-specific evidence; do not assign this calcium response to all NFAT proteins or NFAT5. research_relationship_category: regulation compartment_description: Cytosol and nucleus [ca-loh1996] Calcineurin binds the transcription factor NFAT1 and reversibly regulates its activity (1996). https://pubmed.ncbi.nlm.nih.gov/8631904/ DOI: 10.1074/jbc.271.18.10884
Complete structured claim and evidence
Calcium/calmodulin stimulates autophosphorylation of purified brain CaMKII.
Calcium/calmodulin → Ca2+/calmodulin-dependent protein kinase II family source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic kinase complex
experimental_model
Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays
limitations
Brain holoenzyme assay; does not identify every isoform or phosphorylation site.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mammalia
plain_language
Calcium-bound calmodulin starts CaMKII self-phosphorylation.
primary_references
[ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5
research_relationship_category
regulation
tissue_or_cell_type
Brain enzyme preparation
Calcium: mechanism-first literature curation (2026-09-17) · lines 438–449
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays · source_derived_draft · unverified_draft
### ca-camkii-calmodulin-activation Calcium/calmodulin stimulates autophosphorylation of purified brain CaMKII. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium-bound calmodulin starts CaMKII self-phosphorylation. organism: Mammalia tissue_or_cell_type: Brain enzyme preparation experimental_model: Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays limitations: Brain holoenzyme assay; does not identify every isoform or phosphorylation site. research_relationship_category: regulation compartment_description: Cytosolic kinase complex [ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5
Complete structured claim and evidence
Partial autophosphorylation generates CaMKII activity that persists in the absence of calcium in the purified assay.
Ca2+/calmodulin-dependent protein kinase II family → Autophosphorylated CaMKII with autonomous activity source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic kinase complex
experimental_model
Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays
limitations
Autonomy depends on phosphorylation conditions; not all self-phosphorylation activates and persistence in living cells is not quantified.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mammalia
plain_language
After activation, CaMKII can retain activity beyond the calcium pulse.
primary_references
[ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5
research_relationship_category
protein_modification
tissue_or_cell_type
Brain enzyme preparation
Calcium: mechanism-first literature curation (2026-09-17) · lines 451–462
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays · source_derived_draft · unverified_draft
### ca-camkii-autonomous-activity Partial autophosphorylation generates CaMKII activity that persists in the absence of calcium in the purified assay. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: After activation, CaMKII can retain activity beyond the calcium pulse. organism: Mammalia tissue_or_cell_type: Brain enzyme preparation experimental_model: Purified mammalian brain CaMKII; phosphorylation and substrate-kinase assays limitations: Autonomy depends on phosphorylation conditions; not all self-phosphorylation activates and persistence in living cells is not quantified. research_relationship_category: protein_modification compartment_description: Cytosolic kinase complex [ca-miller1986] Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch (1986). https://pubmed.ncbi.nlm.nih.gov/3006921/ DOI: 10.1016/0092-8674(86)90008-5
Complete structured claim and evidence
Applied IP3 releases calcium from a nonmitochondrial intracellular store in permeabilized pancreatic acinar cells.
IP3 → ER calcium release source_derived_draftungraded
Experimental context and source evidence
compartment_description
Nonmitochondrial intracellular store to cytosol
experimental_model
Permeabilized rat pancreatic acinar cells
limitations
Permeabilized-cell application; receptor isoform and dietary status were not established.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus
plain_language
IP3 releases stored calcium inside acinar cells.
primary_references
[ca-streb1983] Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate (1983). https://pubmed.ncbi.nlm.nih.gov/6605482/ DOI: 10.1038/306067a0
research_relationship_category
mechanism
tissue_or_cell_type
Pancreatic acinar cells
transport_or_reaction_direction
Intracellular store to cytosol
Calcium: mechanism-first literature curation (2026-09-17) · lines 464–476
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Permeabilized rat pancreatic acinar cells · source_derived_draft · unverified_draft
### ca-ip3-mobilizes-store Applied IP3 releases calcium from a nonmitochondrial intracellular store in permeabilized pancreatic acinar cells. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: IP3 releases stored calcium inside acinar cells. organism: Rattus norvegicus tissue_or_cell_type: Pancreatic acinar cells experimental_model: Permeabilized rat pancreatic acinar cells limitations: Permeabilized-cell application; receptor isoform and dietary status were not established. research_relationship_category: mechanism transport_or_reaction_direction: Intracellular store to cytosol compartment_description: Nonmitochondrial intracellular store to cytosol [ca-streb1983] Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate (1983). https://pubmed.ncbi.nlm.nih.gov/6605482/ DOI: 10.1038/306067a0
Complete structured claim and evidence
Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state.
Inositol 1,4,5-trisphosphate receptor type 3 / ITPR3 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
ER membrane
experimental_model
Recombinant human ITPR3; cryo-EM in ligand-bound gating states
limitations
Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
ITPR3 provides a route for calcium to leave the ER.
primary_references
[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2
research_relationship_category
transport
tissue_or_cell_type
Recombinant ITPR3
transport_effect
raises A calcium-release channel: the recorded direction is ER lumen to cytosol.
transport_or_reaction_direction
ER lumen to cytosol
transport_pool
cytosolic calcium A calcium-release channel: the recorded direction is ER lumen to cytosol.
Calcium: mechanism-first literature curation (2026-09-17) · lines 478–490
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft
### ca-itpr3-er-calcium-channel Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ITPR3 provides a route for calcium to leave the ER. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structure specifies ITPR3; it must not be relabeled as ITPR1 or a measurement of every receptor subtype. research_relationship_category: transport transport_or_reaction_direction: ER lumen to cytosol compartment_description: ER membrane [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2
Complete structured claim and evidence
Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved.
Calcium ion → Inositol 1,4,5-trisphosphate receptor type 3 / ITPR3 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic regulatory regions of ER channel
experimental_model
Recombinant human ITPR3; cryo-EM in ligand-bound gating states
limitations
Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open.
primary_references
[ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2
research_relationship_category
regulation
tissue_or_cell_type
Recombinant ITPR3
Calcium: mechanism-first literature curation (2026-09-17) · lines 492–503
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human ITPR3; cryo-EM in ligand-bound gating states · source_derived_draft · unverified_draft
### ca-itpr3-calcium-coactivation Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps control ITPR3 opening; binding does not guarantee that the channel stays open. organism: Homo sapiens tissue_or_cell_type: Recombinant ITPR3 experimental_model: Recombinant human ITPR3; cryo-EM in ligand-bound gating states limitations: Structural populations do not define a universal calcium threshold or prove all calcium-bound channels are active. research_relationship_category: regulation compartment_description: Cytosolic regulatory regions of ER channel [ca-schmitz2022] Structural basis for activation and gating of IP3 receptors (2022). https://pubmed.ncbi.nlm.nih.gov/35301323/ DOI: 10.1038/s41467-022-29073-2
Complete structured claim and evidence
ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region.
STIM1 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
ER lumen and ER-plasma-membrane junctions
experimental_model
Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis
limitations
Local store depletion is a cellular signal, not evidence of dietary calcium deficiency.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
STIM1 detects falling calcium inside the ER.
primary_references
[ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055
research_relationship_category
regulation
tissue_or_cell_type
HeLa cells
Calcium: mechanism-first literature curation (2026-09-17) · lines 505–516
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft
### ca-stim1-store-sensing ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 detects falling calcium inside the ER. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: Local store depletion is a cellular signal, not evidence of dietary calcium deficiency. research_relationship_category: regulation compartment_description: ER lumen and ER-plasma-membrane junctions [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055
Complete structured claim and evidence
STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells.
STIM1 → Store-operated calcium entry source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
ER-plasma-membrane signaling junction
experimental_model
Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis
limitations
RNA interference perturbs signaling machinery; it does not model low calcium intake.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Reducing STIM1 weakens calcium entry after stores empty.
primary_references
[ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055
research_relationship_category
loss_of_function
tissue_or_cell_type
HeLa cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 518–529
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis · source_derived_draft · unverified_draft
### ca-stim1-knockdown-influx STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing STIM1 weakens calcium entry after stores empty. organism: Homo sapiens tissue_or_cell_type: HeLa cells experimental_model: Human HeLa cells; RNA interference screen, calcium imaging and STIM1 EF-hand mutagenesis limitations: RNA interference perturbs signaling machinery; it does not model low calcium intake. research_relationship_category: loss_of_function compartment_description: ER-plasma-membrane signaling junction [ca-liou2005] STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx (2005). https://pubmed.ncbi.nlm.nih.gov/16005298/ DOI: 10.1016/j.cub.2005.05.055
Complete structured claim and evidence
The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current.
STIM1 → ORAI1 source_derived_draftungraded
Experimental context and source evidence
compartment_description
ER-plasma-membrane junctions
experimental_model
Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays
limitations
Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
STIM1 directly opens the ORAI1 calcium-entry pathway.
primary_references
[ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014
research_relationship_category
regulation
tissue_or_cell_type
HEK293 expression system and purified proteins
Calcium: mechanism-first literature curation (2026-09-17) · lines 531–542
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays · source_derived_draft · unverified_draft
### ca-stim1-direct-orai1-gating The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: STIM1 directly opens the ORAI1 calcium-entry pathway. organism: Homo sapiens tissue_or_cell_type: HEK293 expression system and purified proteins experimental_model: Human HEK293/HEK293T expression, electrophysiology and purified protein-binding assays limitations: Domain-expression experiments isolate coupling; physiological amplitude depends on cellular context. research_relationship_category: regulation compartment_description: ER-plasma-membrane junctions [ca-park2009] STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1 (2009). https://pubmed.ncbi.nlm.nih.gov/19249086/ DOI: 10.1016/j.cell.2009.02.014
Complete structured claim and evidence
ORAI1 supplies the calcium-selective CRAC pore; transmembrane substitutions alter calcium and monovalent-ion permeability.
ORAI1 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane
experimental_model
Human ORAI1 mutagenesis and membrane-current/selectivity measurements
limitations
Pore evidence does not specify channel stoichiometry or all tissue contributions.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
ORAI1 forms the pore through which store-operated calcium enters.
primary_references
[ca-prakriya2006] Orai1 is an essential pore subunit of the CRAC channel (2006). https://www.nature.com/articles/nature05122 DOI: 10.1038/nature05122
research_relationship_category
transport
tissue_or_cell_type
Recombinant channel assays
transport_effect
raises The CRAC pore carries calcium from extracellular fluid to cytosol.
transport_or_reaction_direction
Extracellular fluid to cytosol
transport_pool
cytosolic calcium The CRAC pore carries calcium from extracellular fluid to cytosol.
Calcium: mechanism-first literature curation (2026-09-17) · lines 544–556
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human ORAI1 mutagenesis and membrane-current/selectivity measurements · source_derived_draft · unverified_draft
### ca-orai1-calcium-permeation ORAI1 supplies the calcium-selective CRAC pore; transmembrane substitutions alter calcium and monovalent-ion permeability. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ORAI1 forms the pore through which store-operated calcium enters. organism: Homo sapiens tissue_or_cell_type: Recombinant channel assays experimental_model: Human ORAI1 mutagenesis and membrane-current/selectivity measurements limitations: Pore evidence does not specify channel stoichiometry or all tissue contributions. research_relationship_category: transport transport_or_reaction_direction: Extracellular fluid to cytosol compartment_description: Plasma membrane [ca-prakriya2006] Orai1 is an essential pore subunit of the CRAC channel (2006). https://www.nature.com/articles/nature05122 DOI: 10.1038/nature05122
Complete structured claim and evidence
Homozygous ORAI1 R91W loss of function abolishes CRAC activity in patient T cells; wild-type ORAI1 restores influx.
ORAI1 → Store-operated calcium entry source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Plasma membrane
experimental_model
Human inherited immune deficiency, patient T-cell rescue and functional channel assays
limitations
A rare channelopathy, not nutritional calcium deficiency; the evidence concerns the studied variant.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
This inherited channel defect interrupts calcium entry into T cells.
primary_references
[ca-feske2006] A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function (2006). https://pubmed.ncbi.nlm.nih.gov/16582901/ DOI: 10.1038/nature04702
research_relationship_category
loss_of_function
tissue_or_cell_type
Patient T lymphocytes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 558–569
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human inherited immune deficiency, patient T-cell rescue and functional channel assays · source_derived_draft · unverified_draft
### ca-orai1-inherited-loss-influx Homozygous ORAI1 R91W loss of function abolishes CRAC activity in patient T cells; wild-type ORAI1 restores influx. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This inherited channel defect interrupts calcium entry into T cells. organism: Homo sapiens tissue_or_cell_type: Patient T lymphocytes experimental_model: Human inherited immune deficiency, patient T-cell rescue and functional channel assays limitations: A rare channelopathy, not nutritional calcium deficiency; the evidence concerns the studied variant. research_relationship_category: loss_of_function compartment_description: Plasma membrane [ca-feske2006] A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function (2006). https://pubmed.ncbi.nlm.nih.gov/16582901/ DOI: 10.1038/nature04702
Complete structured claim and evidence
Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER.
SERCA2 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
ER membrane
experimental_model
Purified recombinant human SERCA2b; cryo-EM and ATPase characterization
limitations
Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
SERCA2b uses ATP to refill ER calcium stores.
primary_references
[ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147
research_relationship_category
transport
tissue_or_cell_type
Recombinant SERCA2b
transport_effect
lowers Recorded as sequestration of cytosolic calcium into the ER.
transport_or_reaction_direction
Cytosol to ER lumen
transport_pool
cytosolic calcium Recorded as sequestration of cytosolic calcium into the ER.
Calcium: mechanism-first literature curation (2026-09-17) · lines 571–583
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human SERCA2b; cryo-EM and ATPase characterization · source_derived_draft · unverified_draft
### ca-serca2b-er-uptake Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: SERCA2b uses ATP to refill ER calcium stores. organism: Homo sapiens tissue_or_cell_type: Recombinant SERCA2b experimental_model: Purified recombinant human SERCA2b; cryo-EM and ATPase characterization limitations: Evidence specifies ATP2A2 splice isoform SERCA2b; kinetic properties should not be assigned to every SERCA isoform. research_relationship_category: transport transport_or_reaction_direction: Cytosol to ER lumen compartment_description: ER membrane [ca-zhang2020] Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail (2020). https://pubmed.ncbi.nlm.nih.gov/32851169/ DOI: 10.1126/sciadv.abb0147
Complete structured claim and evidence
Human PMCA1 is an ATP-driven plasma-membrane calcium extrusion pump characterized structurally with neuroplastin.
Plasma membrane calcium ATPase 1 / ATP2B1 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane
experimental_model
Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays
limitations
This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
PMCA1 uses ATP to clear calcium from the cytosol.
primary_references
[ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7
research_relationship_category
transport
tissue_or_cell_type
Purified recombinant pump
transport_effect
lowers Recorded as an ATP-driven plasma-membrane calcium extrusion pump.
transport_or_reaction_direction
Cytosol to extracellular fluid
transport_pool
cytosolic calcium Recorded as an ATP-driven plasma-membrane calcium extrusion pump.
Calcium: mechanism-first literature curation (2026-09-17) · lines 585–597
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays · source_derived_draft · unverified_draft
### ca-pmca1-extrusion Human PMCA1 is an ATP-driven plasma-membrane calcium extrusion pump characterized structurally with neuroplastin. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PMCA1 uses ATP to clear calcium from the cytosol. organism: Homo sapiens tissue_or_cell_type: Purified recombinant pump experimental_model: Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays limitations: This study combines structure and ATPase assays; it does not quantify whole-tissue extrusion flux. research_relationship_category: transport transport_or_reaction_direction: Cytosol to extracellular fluid compartment_description: Plasma membrane [ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7
Complete structured claim and evidence
Neuroplastin binds the transmembrane region of human PMCA1 and supports pump ATPase activity.
Neuroplastin / NPTN → Plasma membrane calcium ATPase 1 / ATP2B1 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane protein complex
experimental_model
Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays
limitations
Purified PMCA1 complex; subunit availability and other PMCA isoforms require separate evidence.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Neuroplastin helps PMCA1 function.
primary_references
[ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7
research_relationship_category
regulation
tissue_or_cell_type
Purified recombinant proteins
Calcium: mechanism-first literature curation (2026-09-17) · lines 599–610
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays · source_derived_draft · unverified_draft
### ca-neuroplastin-pmca1-support Neuroplastin binds the transmembrane region of human PMCA1 and supports pump ATPase activity. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Neuroplastin helps PMCA1 function. organism: Homo sapiens tissue_or_cell_type: Purified recombinant proteins experimental_model: Purified human PMCA1-neuroplastin complex; cryo-EM and ATPase assays limitations: Purified PMCA1 complex; subunit availability and other PMCA isoforms require separate evidence. research_relationship_category: regulation compartment_description: Plasma membrane protein complex [ca-gong2018] Structure of the human plasma membrane Ca2+-ATPase 1 in complex with its obligatory subunit neuroplastin (2018). https://pubmed.ncbi.nlm.nih.gov/30190470/ DOI: 10.1038/s41467-018-06075-7
Complete structured claim and evidence
Calmodulin increases apparent calcium affinity and ATPase activity of the erythrocyte calcium pump.
Calcium/calmodulin → Plasma membrane calcium ATPase family source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane
experimental_model
Human erythrocyte membrane ghosts with purified human or bovine calmodulin
limitations
Membrane ghosts with controlled additions; pump isoforms were not resolved and this is not an intact-cell dose response.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calmodulin makes the red-cell calcium pump respond more strongly to calcium.
primary_references
[ca-roufogalis1980] Regulation by calmodulin of the calcium affinity of the calcium-transport ATPase in human erythrocytes (1980). https://pubmed.ncbi.nlm.nih.gov/6109558/ DOI: 10.1139/o80-126
research_relationship_category
regulation
tissue_or_cell_type
Erythrocyte membranes
Calcium: mechanism-first literature curation (2026-09-17) · lines 612–623
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human erythrocyte membrane ghosts with purified human or bovine calmodulin · source_derived_draft · unverified_draft
### ca-calmodulin-pmca-affinity Calmodulin increases apparent calcium affinity and ATPase activity of the erythrocyte calcium pump. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calmodulin makes the red-cell calcium pump respond more strongly to calcium. organism: Homo sapiens tissue_or_cell_type: Erythrocyte membranes experimental_model: Human erythrocyte membrane ghosts with purified human or bovine calmodulin limitations: Membrane ghosts with controlled additions; pump isoforms were not resolved and this is not an intact-cell dose response. research_relationship_category: regulation compartment_description: Plasma membrane [ca-roufogalis1980] Regulation by calmodulin of the calcium affinity of the calcium-transport ATPase in human erythrocytes (1980). https://pubmed.ncbi.nlm.nih.gov/6109558/ DOI: 10.1139/o80-126
Complete structured claim and evidence
Human cardiac NCX1 exchanges calcium and sodium in opposing directions across the membrane.
Na+/Ca2+ exchanger 1 / SLC8A1 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane
experimental_model
Human cardiac NCX1; cryo-EM and functional exchange assays
limitations
Net direction depends on electrochemical gradients and voltage; NCX1 is not an ATP-hydrolyzing pump.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
NCX1 couples calcium movement to sodium moving the other way.
primary_references
[ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4
research_relationship_category
transport
tissue_or_cell_type
Cardiac NCX1 expression system
transport_effect
depends Reversible exchange: forward mode extrudes calcium and reverse mode admits it, which the record states.
transport_or_reaction_direction
Reversible Na+/Ca2+ exchange; forward calcium extrusion or reverse calcium entry
transport_pool
cytosolic calcium Reversible exchange: forward mode extrudes calcium and reverse mode admits it, which the record states.
Calcium: mechanism-first literature curation (2026-09-17) · lines 625–637
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cardiac NCX1; cryo-EM and functional exchange assays · source_derived_draft · unverified_draft
### ca-ncx1-calcium-sodium-exchange Human cardiac NCX1 exchanges calcium and sodium in opposing directions across the membrane. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: NCX1 couples calcium movement to sodium moving the other way. organism: Homo sapiens tissue_or_cell_type: Cardiac NCX1 expression system experimental_model: Human cardiac NCX1; cryo-EM and functional exchange assays limitations: Net direction depends on electrochemical gradients and voltage; NCX1 is not an ATP-hydrolyzing pump. research_relationship_category: transport transport_or_reaction_direction: Reversible Na+/Ca2+ exchange; forward calcium extrusion or reverse calcium entry compartment_description: Plasma membrane [ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4
Complete structured claim and evidence
Calcium binding to the cytosolic CBD2 regulatory domain disrupts an inactive NCX1 assembly and permits exchange.
Calcium ion → Na+/Ca2+ exchanger 1 / SLC8A1 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic regulatory domain of plasma-membrane exchanger
experimental_model
Human cardiac NCX1; cryo-EM and functional exchange assays
limitations
Regulatory calcium binding is distinct from calcium being transported; the measured splice form and assay conditions matter.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calcium also regulates NCX1 at a site separate from the transported-ion pathway.
primary_references
[ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4
research_relationship_category
regulation
tissue_or_cell_type
Cardiac NCX1 expression system
Calcium: mechanism-first literature curation (2026-09-17) · lines 639–650
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cardiac NCX1; cryo-EM and functional exchange assays · source_derived_draft · unverified_draft
### ca-ncx1-regulatory-calcium Calcium binding to the cytosolic CBD2 regulatory domain disrupts an inactive NCX1 assembly and permits exchange. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium also regulates NCX1 at a site separate from the transported-ion pathway. organism: Homo sapiens tissue_or_cell_type: Cardiac NCX1 expression system experimental_model: Human cardiac NCX1; cryo-EM and functional exchange assays limitations: Regulatory calcium binding is distinct from calcium being transported; the measured splice form and assay conditions matter. research_relationship_category: regulation compartment_description: Cytosolic regulatory domain of plasma-membrane exchanger [ca-xue2023] Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1 (2023). https://pubmed.ncbi.nlm.nih.gov/37794011/ DOI: 10.1038/s41467-023-41885-4
Complete structured claim and evidence
Purified skeletal-muscle RyR1 forms an intracellular calcium-release channel with ligand-dependent open and closed states.
Ryanodine receptor 1 / RYR1 → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
Sarcoplasmic reticulum membrane
experimental_model
Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings
limitations
Reconstituted channel; the study does not reconstruct voltage-sensor coupling in an intact muscle.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Oryctolagus cuniculus
plain_language
RyR1 supplies the skeletal-muscle calcium-release pathway.
primary_references
[ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075
research_relationship_category
transport
tissue_or_cell_type
Skeletal muscle
transport_effect
raises An intracellular calcium-release channel: the recorded direction is SR lumen to cytosol.
transport_or_reaction_direction
SR lumen to cytosol
transport_pool
cytosolic calcium An intracellular calcium-release channel: the recorded direction is SR lumen to cytosol.
Calcium: mechanism-first literature curation (2026-09-17) · lines 652–664
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings · source_derived_draft · unverified_draft
### ca-ryr1-calcium-release Purified skeletal-muscle RyR1 forms an intracellular calcium-release channel with ligand-dependent open and closed states. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: RyR1 supplies the skeletal-muscle calcium-release pathway. organism: Oryctolagus cuniculus tissue_or_cell_type: Skeletal muscle experimental_model: Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings limitations: Reconstituted channel; the study does not reconstruct voltage-sensor coupling in an intact muscle. research_relationship_category: transport transport_or_reaction_direction: SR lumen to cytosol compartment_description: Sarcoplasmic reticulum membrane [ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075
Complete structured claim and evidence
Calcium binds an activating RyR1 site and primes gating; ATP and caffeine increase open-state representation in the experimental preparation.
Calcium ion → Ryanodine receptor 1 / RYR1 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosolic channel-regulatory region
experimental_model
Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings
limitations
Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Oryctolagus cuniculus
plain_language
Calcium helps regulate the RyR1 gate.
primary_references
[ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075
research_relationship_category
regulation
tissue_or_cell_type
Skeletal-muscle channel preparation
Calcium: mechanism-first literature curation (2026-09-17) · lines 666–677
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings · source_derived_draft · unverified_draft
### ca-ryr1-calcium-gating Calcium binds an activating RyR1 site and primes gating; ATP and caffeine increase open-state representation in the experimental preparation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps regulate the RyR1 gate. organism: Oryctolagus cuniculus tissue_or_cell_type: Skeletal-muscle channel preparation experimental_model: Purified rabbit skeletal-muscle RyR1 with calstabin2; cryo-EM and planar-bilayer recordings limitations: Calcium is both a transported ion and a ligand; caffeine-assisted structures do not imply caffeine is required physiologically. research_relationship_category: regulation compartment_description: Cytosolic channel-regulatory region [ca-desgeorges2016] Structural Basis for Gating and Activation of RyR1 (2016). https://pubmed.ncbi.nlm.nih.gov/27662087/ DOI: 10.1016/j.cell.2016.08.075
Complete structured claim and evidence
MCU supplies the inner-mitochondrial-membrane calcium-conducting pore and promotes agonist-evoked matrix calcium uptake.
Mitochondrial calcium uniporter pore protein / MCU → Calcium ion source_derived_draftungraded
Experimental context and source evidence
compartment_description
Inner mitochondrial membrane
experimental_model
Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers
limitations
Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
MCU lets calcium enter the mitochondrial matrix.
primary_references
[ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230
research_relationship_category
transport
tissue_or_cell_type
HeLa cells and purified channel
transport_effect
raises Recorded as promoting agonist-evoked matrix calcium uptake.
transport_or_reaction_direction
Intermembrane space to mitochondrial matrix
transport_pool
mitochondrial matrix calcium Recorded as promoting agonist-evoked matrix calcium uptake.
Calcium: mechanism-first literature curation (2026-09-17) · lines 679–691
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers · source_derived_draft · unverified_draft
### ca-mcu-matrix-uptake MCU supplies the inner-mitochondrial-membrane calcium-conducting pore and promotes agonist-evoked matrix calcium uptake. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MCU lets calcium enter the mitochondrial matrix. organism: Homo sapiens tissue_or_cell_type: HeLa cells and purified channel experimental_model: Human HeLa MCU silencing/overexpression and purified MCU in planar bilayers limitations: Pore and overexpression evidence; native uptake also depends on accessory subunits and membrane potential. research_relationship_category: transport transport_or_reaction_direction: Intermembrane space to mitochondrial matrix compartment_description: Inner mitochondrial membrane [ca-destefani2011] A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685888/ DOI: 10.1038/nature10230
Complete structured claim and evidence
MCU silencing sharply reduces mitochondrial calcium uptake while membrane potential and respiration remain intact in the tested preparations.
Mitochondrial calcium uniporter pore protein / MCU → Mitochondrial calcium uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Inner mitochondrial membrane
experimental_model
Cultured mammalian cells and in vivo mouse-liver MCU silencing
limitations
No inference of universal respiratory failure or dietary calcium deficiency.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens and Mus musculus
plain_language
Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion.
primary_references
[ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234
research_relationship_category
loss_of_function
tissue_or_cell_type
Cultured cells and mouse liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 693–704
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cultured mammalian cells and in vivo mouse-liver MCU silencing · source_derived_draft · unverified_draft
### ca-mcu-loss-matrix-uptake MCU silencing sharply reduces mitochondrial calcium uptake while membrane potential and respiration remain intact in the tested preparations. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion. organism: Homo sapiens and Mus musculus tissue_or_cell_type: Cultured cells and mouse liver experimental_model: Cultured mammalian cells and in vivo mouse-liver MCU silencing limitations: No inference of universal respiratory failure or dietary calcium deficiency. research_relationship_category: loss_of_function compartment_description: Inner mitochondrial membrane [ca-baughman2011] Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter (2011). https://pubmed.ncbi.nlm.nih.gov/21685886/ DOI: 10.1038/nature10234
Complete structured claim and evidence
MICU1 limits MCU-dependent calcium uptake at low external calcium in the examined cell preparations.
Mitochondrial calcium uptake protein 1 / MICU1 → Mitochondrial calcium uptake source_derived_draftungraded
Experimental context and source evidence
compartment_description
Mitochondrial uniporter regulatory machinery
experimental_model
HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays
limitations
Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria.
primary_references
[ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011
research_relationship_category
regulation
tissue_or_cell_type
HeLa, HEK293 and endothelial cells
Calcium: mechanism-first literature curation (2026-09-17) · lines 706–717
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays · source_derived_draft · unverified_draft
### ca-micu1-basal-uptake-restraint MICU1 limits MCU-dependent calcium uptake at low external calcium in the examined cell preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MICU1 helps prevent unnecessary calcium accumulation in resting mitochondria. organism: Homo sapiens tissue_or_cell_type: HeLa, HEK293 and endothelial cells experimental_model: HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays limitations: Threshold and molecular explanation are assay-dependent; see the separate MICU1 gating conflict. research_relationship_category: regulation compartment_description: Mitochondrial uniporter regulatory machinery [ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011
Complete structured claim and evidence
MICU1 knockdown elevates basal matrix calcium through MCU-dependent uptake in the tested cells.
Mitochondrial calcium uptake protein 1 / MICU1 → Mitochondrial calcium overload source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Mitochondrial matrix
experimental_model
HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays
limitations
Cell-specific knockdown response; does not imply high dietary calcium or all MICU1 variants behave identically.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Loss of MICU1 can let mitochondria accumulate too much calcium at rest.
primary_references
[ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011
research_relationship_category
loss_of_function
tissue_or_cell_type
HeLa and endothelial cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 719–730
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays · source_derived_draft · unverified_draft
### ca-micu1-loss-overload MICU1 knockdown elevates basal matrix calcium through MCU-dependent uptake in the tested cells. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of MICU1 can let mitochondria accumulate too much calcium at rest. organism: Homo sapiens tissue_or_cell_type: HeLa and endothelial cells experimental_model: HeLa, HEK293 and human endothelial-cell knockdown; calcium-flux and stress assays limitations: Cell-specific knockdown response; does not imply high dietary calcium or all MICU1 variants behave identically. research_relationship_category: loss_of_function compartment_description: Mitochondrial matrix [ca-mallilankaraman2012] MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca2+ uptake that regulates cell survival (2012). https://pubmed.ncbi.nlm.nih.gov/23101630/ DOI: 10.1016/j.cell.2012.10.011
Complete structured claim and evidence
Calcium-responsive EF hands in MICU1 and MICU2 allow the uniporter to pass from restrained low-calcium uptake to uptake above a threshold.
Calcium ion → Mitochondrial calcium uniporter complex source_derived_draftungraded
Experimental context and source evidence
compartment_description
Mitochondrial intermembrane-space regulatory subunits
experimental_model
Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance
limitations
Knockout/rescue and permeabilized-cell evidence; numeric thresholds are not universal.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
MICU1 and MICU2 help the uniporter distinguish small calcium levels from a signal.
primary_references
[ca-kamer2014] MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter (2014). https://pubmed.ncbi.nlm.nih.gov/24503055/ DOI: 10.1002/embr.201337946
research_relationship_category
regulation
tissue_or_cell_type
HEK293T cells
Calcium: mechanism-first literature curation (2026-09-17) · lines 732–743
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance · source_derived_draft · unverified_draft
### ca-micu12-calcium-sensing Calcium-responsive EF hands in MICU1 and MICU2 allow the uniporter to pass from restrained low-calcium uptake to uptake above a threshold. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: MICU1 and MICU2 help the uniporter distinguish small calcium levels from a signal. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: Human HEK293T MICU1/MICU2 knockout and EF-hand mutant rescue; permeabilized-cell calcium clearance limitations: Knockout/rescue and permeabilized-cell evidence; numeric thresholds are not universal. research_relationship_category: regulation compartment_description: Mitochondrial intermembrane-space regulatory subunits [ca-kamer2014] MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter (2014). https://pubmed.ncbi.nlm.nih.gov/24503055/ DOI: 10.1002/embr.201337946
Complete structured claim and evidence
Garg and colleagues interpret mitochondrial currents as MICU-dependent enhancement of uniporter opening at elevated external calcium, without pore occlusion.
Mitochondrial calcium uptake protein 1 / MICU1 → Mitochondrial calcium uniporter complex source_derived_draftungraded
Experimental context and source evidence
compartment_description
Inner mitochondrial membrane
experimental_model
Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp
limitations
Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mammalia
plain_language
One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals.
primary_references
[ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312
tissue_or_cell_type
Isolated mitochondria and mitoplasts
Calcium: mechanism-first literature curation (2026-09-17) · lines 745–755
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp · source_derived_draft · unverified_draft
### ca-micu-potentiation-model Garg and colleagues interpret mitochondrial currents as MICU-dependent enhancement of uniporter opening at elevated external calcium, without pore occlusion. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: One electrophysiological study proposes that MICU proteins increase channel opening during calcium signals. organism: Mammalia tissue_or_cell_type: Isolated mitochondria and mitoplasts experimental_model: Isolated mammalian mitochondria and mitoplast macroscopic/single-channel patch clamp limitations: Contested interpretation; mitoplast preparation and subunit abundance are challenged by Tsai 2023. Not a settled universal edge. compartment_description: Inner mitochondrial membrane [ca-garg2021] The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter (2021). https://pubmed.ncbi.nlm.nih.gov/34463251/ DOI: 10.7554/eLife.69312
Complete structured claim and evidence
Purified MICU1 suppresses MCU-complex currents in patch-clamp experiments, and disruption of its MCU-interacting K126 residue abolishes this suppression.
Mitochondrial calcium uptake protein 1 / MICU1 → Mitochondrial calcium uniporter complex source_derived_draftungraded
Experimental context and source evidence
compartment_description
Intermembrane-space face of inner mitochondrial membrane
experimental_model
Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays
limitations
Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mammalia
plain_language
A later study directly observes MICU1 inhibiting the uniporter.
primary_references
[ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120
research_relationship_category
mechanistic_evidence
tissue_or_cell_type
Reconstituted protein and mitochondrial preparations
Calcium: mechanism-first literature curation (2026-09-17) · lines 757–768
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays · source_derived_draft · unverified_draft
### ca-micu1-occlusion-evidence Purified MICU1 suppresses MCU-complex currents in patch-clamp experiments, and disruption of its MCU-interacting K126 residue abolishes this suppression. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A later study directly observes MICU1 inhibiting the uniporter. organism: Mammalia tissue_or_cell_type: Reconstituted protein and mitochondrial preparations experimental_model: Purified MICU1 addition, mitoplast patch clamp and intact mitochondrial ion-flux assays limitations: Supports pore occlusion in these assays; competing potentiation evidence remains linked rather than discarded. research_relationship_category: mechanistic_evidence compartment_description: Intermembrane-space face of inner mitochondrial membrane [ca-tsai2023] Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex (2023). https://pubmed.ncbi.nlm.nih.gov/37036971/ DOI: 10.1073/pnas.2217665120
Complete structured claim and evidence
Calcium binds the regulatory site of cardiac troponin C; the calcium-loaded ternary structure supports altered inhibitory troponin-I interactions with actin.
Calcium ion → Cardiac and slow skeletal troponin C / TNNC1 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Sarcomeric thin-filament regulatory complex
experimental_model
Purified human cardiac troponin ternary core; crystallography
limitations
Actin-disengagement is a structural model; this is not a direct whole-heart force measurement or a smooth-muscle mechanism.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Troponin C senses calcium to regulate cardiac contraction.
primary_references
[ca-takeda2003] Structure of the core domain of human cardiac troponin in the Ca2+-saturated form (2003). https://pubmed.ncbi.nlm.nih.gov/12840750/ DOI: 10.1038/nature01780
research_relationship_category
binding
tissue_or_cell_type
Cardiac troponin core
Calcium: mechanism-first literature curation (2026-09-17) · lines 770–781
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cardiac troponin ternary core; crystallography · source_derived_draft · unverified_draft
### ca-cardiac-troponin-calcium-switch Calcium binds the regulatory site of cardiac troponin C; the calcium-loaded ternary structure supports altered inhibitory troponin-I interactions with actin. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Troponin C senses calcium to regulate cardiac contraction. organism: Homo sapiens tissue_or_cell_type: Cardiac troponin core experimental_model: Purified human cardiac troponin ternary core; crystallography limitations: Actin-disengagement is a structural model; this is not a direct whole-heart force measurement or a smooth-muscle mechanism. research_relationship_category: binding compartment_description: Sarcomeric thin-filament regulatory complex [ca-takeda2003] Structure of the core domain of human cardiac troponin in the Ca2+-saturated form (2003). https://pubmed.ncbi.nlm.nih.gov/12840750/ DOI: 10.1038/nature01780
Complete structured claim and evidence
Calcium binding to synaptotagmin 1 participates in triggering evoked neurotransmitter release at mouse synapses.
Calcium ion → Evoked synaptic vesicle release source_derived_draftungraded
Experimental context and source evidence
compartment_description
Presynaptic vesicle-plasma-membrane interface
experimental_model
Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements
limitations
SYT1-dependent evoked release; does not establish the sensor for every secretory cell or all release modes.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Synaptotagmin 1 helps convert a calcium signal into vesicle release.
primary_references
[ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004
research_relationship_category
regulation
tissue_or_cell_type
Cultured neurons
Calcium: mechanism-first literature curation (2026-09-17) · lines 783–794
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements · source_derived_draft · unverified_draft
### ca-synaptotagmin-calcium-release Calcium binding to synaptotagmin 1 participates in triggering evoked neurotransmitter release at mouse synapses. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Synaptotagmin 1 helps convert a calcium signal into vesicle release. organism: Mus musculus tissue_or_cell_type: Cultured neurons experimental_model: Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements limitations: SYT1-dependent evoked release; does not establish the sensor for every secretory cell or all release modes. research_relationship_category: regulation compartment_description: Presynaptic vesicle-plasma-membrane interface [ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004
Complete structured claim and evidence
A synaptotagmin-1 knock-in mutation reducing calcium affinity also reduces the calcium sensitivity of evoked neurotransmitter release.
Synaptotagmin 1 / SYT1 → Evoked synaptic vesicle release source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Presynaptic terminal
experimental_model
Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements
limitations
Readily releasable pool size and spontaneous release were unchanged; this is a sensor mutation, not calcium deprivation.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Changing the calcium sensor changes the calcium needed to trigger release.
primary_references
[ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004
research_relationship_category
loss_of_function
tissue_or_cell_type
Cultured neurons
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 796–807
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements · source_derived_draft · unverified_draft
### ca-synaptotagmin-mutant-sensitivity A synaptotagmin-1 knock-in mutation reducing calcium affinity also reduces the calcium sensitivity of evoked neurotransmitter release. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the calcium sensor changes the calcium needed to trigger release. organism: Mus musculus tissue_or_cell_type: Cultured neurons experimental_model: Mouse synaptotagmin-1 knock-in and cultured neuronal release measurements limitations: Readily releasable pool size and spontaneous release were unchanged; this is a sensor mutation, not calcium deprivation. research_relationship_category: loss_of_function compartment_description: Presynaptic terminal [ca-fernandezchacon2001] Synaptotagmin I functions as a calcium regulator of release probability (2001). https://pubmed.ncbi.nlm.nih.gov/11242035/ DOI: 10.1038/35065004
Complete structured claim and evidence
Localized sarcoplasmic-reticulum calcium release generates brief calcium sparks in rat cardiac myocytes.
Sarcoplasmic reticulum calcium release → Cardiac calcium sparks source_derived_draftungraded
Experimental context and source evidence
compartment_description
SR to local cytosol
experimental_model
Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations
limitations
Imaging and ryanodine sensitivity establish localized release; the historical single-channel estimate is not encoded as settled channel stoichiometry.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus
plain_language
Heart cells release small local bursts of stored calcium.
primary_references
[ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594
research_relationship_category
mechanism
tissue_or_cell_type
Cardiac myocytes
transport_or_reaction_direction
SR lumen to cytosol
Calcium: mechanism-first literature curation (2026-09-17) · lines 809–821
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations · source_derived_draft · unverified_draft
### ca-cardiac-sr-sparks Localized sarcoplasmic-reticulum calcium release generates brief calcium sparks in rat cardiac myocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Heart cells release small local bursts of stored calcium. organism: Rattus norvegicus tissue_or_cell_type: Cardiac myocytes experimental_model: Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations limitations: Imaging and ryanodine sensitivity establish localized release; the historical single-channel estimate is not encoded as settled channel stoichiometry. research_relationship_category: mechanism transport_or_reaction_direction: SR lumen to cytosol compartment_description: SR to local cytosol [ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594
Complete structured claim and evidence
Increasing sarcoplasmic-reticulum calcium content raises spontaneous release activity and permits some sparks to initiate propagating calcium waves.
Calcium ion → Propagating cardiac calcium waves source_derived_draftungraded
Experimental context and source evidence
compartment_description
SR and cytosol
experimental_model
Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations
limitations
Experimental intracellular store loading, not dietary intake; normal schema category denotes a mechanistic experiment, not a healthy exposure.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Rattus norvegicus
plain_language
Heavily loaded stores can turn local calcium bursts into spreading waves.
primary_references
[ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594
research_relationship_category
exposure_response
tissue_or_cell_type
Quiescent cardiac myocytes under experimental SR loading
Calcium: mechanism-first literature curation (2026-09-17) · lines 823–834
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations · source_derived_draft · unverified_draft
### ca-sr-overload-propagating-waves Increasing sarcoplasmic-reticulum calcium content raises spontaneous release activity and permits some sparks to initiate propagating calcium waves. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Heavily loaded stores can turn local calcium bursts into spreading waves. organism: Rattus norvegicus tissue_or_cell_type: Quiescent cardiac myocytes under experimental SR loading experimental_model: Quiescent rat cardiac myocytes; confocal calcium imaging with ryanodine and SR-loading manipulations limitations: Experimental intracellular store loading, not dietary intake; normal schema category denotes a mechanistic experiment, not a healthy exposure. research_relationship_category: exposure_response compartment_description: SR and cytosol [ca-cheng1993] Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle (1993). https://pubmed.ncbi.nlm.nih.gov/8235594/ DOI: 10.1126/science.8235594
Complete structured claim and evidence
Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations.
Calcium ion → Mitochondrial permeability transition source_derived_draftungraded
Experimental context and source evidence
compartment_description
Inner mitochondrial membrane and matrix
experimental_model
Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts
limitations
Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Excess mitochondrial calcium can trigger membrane permeability failure.
primary_references
[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
research_relationship_category
exposure_response
tissue_or_cell_type
Isolated liver, heart and brain mitochondria
Calcium: mechanism-first literature curation (2026-09-17) · lines 836–847
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft
### ca-overload-permeability-transition Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Excess mitochondrial calcium can trigger membrane permeability failure. organism: Mus musculus tissue_or_cell_type: Isolated liver, heart and brain mitochondria experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Experimental overload; not all apoptosis uses this pathway and the study does not settle the molecular identity of the pore. research_relationship_category: exposure_response compartment_description: Inner mitochondrial membrane and matrix [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
Complete structured claim and evidence
Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type.
Mitochondrial cyclophilin D / PPIF → Calcium overload-induced cell death source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
compartment_description
Mitochondrial permeability-transition pathway
experimental_model
Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts
limitations
Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Removing cyclophilin D protects these cells against calcium-overload injury.
primary_references
[ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
research_relationship_category
loss_of_function
tissue_or_cell_type
Primary hepatocytes and fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 849–860
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts · source_derived_draft · unverified_draft
### ca-ppif-loss-calcium-death-resistance Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing cyclophilin D protects these cells against calcium-overload injury. organism: Mus musculus tissue_or_cell_type: Primary hepatocytes and fibroblasts experimental_model: Ppif-null and cyclophilin-D-overexpressing mice; isolated mitochondria, hepatocytes and fibroblasts limitations: Protection does not extend to all classical apoptotic stimuli; calcium nutrition was not manipulated. research_relationship_category: loss_of_function compartment_description: Mitochondrial permeability-transition pathway [ca-baines2005] Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death (2005). https://pubmed.ncbi.nlm.nih.gov/15800627/ DOI: 10.1038/nature03434
Complete structured claim and evidence
Mature zebrafish fin-ray bone contains crystalline carbonated apatite platelets embedded in an organized collagen matrix.
Hydroxyapatite / biological substituted apatite → Bone extracellular matrix source_derived_draftungraded
Experimental context and source evidence
compartment_description
Bone extracellular matrix
experimental_model
Microscopy, diffraction and elemental analysis
limitations
Biological apatite is substituted and nonstoichiometric; the ideal hydroxyapatite formula is not an exact tissue composition.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Danio rerio
plain_language
Bone contains calcium in a solid mineral phase, distinct from dissolved calcium ions.
primary_references
[mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105
tissue_or_cell_type
Fin-ray bone
Calcium: mechanism-first literature curation (2026-09-17) · lines 862–872
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Microscopy, diffraction and elemental analysis · source_derived_draft · unverified_draft
### bone-calcium-in-solid-apatite Mature zebrafish fin-ray bone contains crystalline carbonated apatite platelets embedded in an organized collagen matrix. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bone contains calcium in a solid mineral phase, distinct from dissolved calcium ions. organism: Danio rerio tissue_or_cell_type: Fin-ray bone experimental_model: Microscopy, diffraction and elemental analysis limitations: Biological apatite is substituted and nonstoichiometric; the ideal hydroxyapatite formula is not an exact tissue composition. compartment_description: Bone extracellular matrix [mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105
Complete structured claim and evidence
Amorphous calcium phosphate in newly forming zebrafish fin bone and increasing crystallinity with maturation support an amorphous-precursor model.
Amorphous calcium phosphate → Hydroxyapatite / biological substituted apatite source_derived_draftungraded
Experimental context and source evidence
compartment_description
Bone extracellular matrix
experimental_model
Spatial maturation series and extracted-particle crystallization
limitations
The proposed sequence is not direct tracking of every mineral particle in living human bone.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Danio rerio
plain_language
A disordered calcium phosphate phase may precede organized bone crystals.
primary_references
[mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105
tissue_or_cell_type
Growing fin-ray bone
Calcium: mechanism-first literature curation (2026-09-17) · lines 874–884
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Spatial maturation series and extracted-particle crystallization · source_derived_draft · unverified_draft
### bone-amorphous-mineral-precursor-hypothesis Amorphous calcium phosphate in newly forming zebrafish fin bone and increasing crystallinity with maturation support an amorphous-precursor model. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A disordered calcium phosphate phase may precede organized bone crystals. organism: Danio rerio tissue_or_cell_type: Growing fin-ray bone experimental_model: Spatial maturation series and extracted-particle crystallization limitations: The proposed sequence is not direct tracking of every mineral particle in living human bone. compartment_description: Bone extracellular matrix [mahamid2008] Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: Indications for an amorphous precursor phase (2008). https://pmc.ncbi.nlm.nih.gov/articles/PMC2529085/ DOI: 10.1073/pnas.0803354105
Complete structured claim and evidence
Human enamel crystallites have an apatite lattice containing calcium and phosphate, with heterogeneous magnesium, sodium, fluoride and carbonate substitutions.
Hydroxyapatite / biological substituted apatite → Tooth enamel source_derived_draftungraded
Experimental context and source evidence
experimental_model
Atomic-scale imaging and correlative spectroscopy
limitations
A structural tissue study; it does not test dietary calcium intake or enamel regeneration.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Tooth enamel is built from chemically varied calcium phosphate crystals.
primary_references
[derocher2020] Chemical gradients in human enamel crystallites (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC8290891/ DOI: 10.1038/s41586-020-2433-3
tissue_or_cell_type
Dental enamel
Calcium: mechanism-first literature curation (2026-09-17) · lines 886–895
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Atomic-scale imaging and correlative spectroscopy · source_derived_draft · unverified_draft
### enamel-calcium-in-substituted-apatite Human enamel crystallites have an apatite lattice containing calcium and phosphate, with heterogeneous magnesium, sodium, fluoride and carbonate substitutions. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tooth enamel is built from chemically varied calcium phosphate crystals. organism: Homo sapiens tissue_or_cell_type: Dental enamel experimental_model: Atomic-scale imaging and correlative spectroscopy limitations: A structural tissue study; it does not test dietary calcium intake or enamel regeneration. [derocher2020] Chemical gradients in human enamel crystallites (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC8290891/ DOI: 10.1038/s41586-020-2433-3
Complete structured claim and evidence
Human PHOSPHO1 hydrolyzes phosphoethanolamine, releasing inorganic phosphate and ethanolamine; the enzyme requires Mg2+ in the assay.
Phosphoethanolamine → Inorganic phosphate (Pi; protonation depends on pH) source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified-enzyme substrate assay
limitations
Catalytic capacity does not quantify phosphate supply in vivo; Pi denotes pH-dependent protonation states.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
PHOSPHO1 can release phosphate from a membrane-headgroup metabolite.
primary_references
[roberts2004] Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities (2004). https://pubmed.ncbi.nlm.nih.gov/15175005/ DOI: 10.1042/BJ20040511
tissue_or_cell_type
Recombinant enzyme; mineralizing-cell context
Calcium: mechanism-first literature curation (2026-09-17) · lines 897–906
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified-enzyme substrate assay · source_derived_draft · unverified_draft
### phospho1-phosphoethanolamine-hydrolysis Human PHOSPHO1 hydrolyzes phosphoethanolamine, releasing inorganic phosphate and ethanolamine; the enzyme requires Mg2+ in the assay. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: PHOSPHO1 can release phosphate from a membrane-headgroup metabolite. organism: Homo sapiens tissue_or_cell_type: Recombinant enzyme; mineralizing-cell context experimental_model: Purified-enzyme substrate assay limitations: Catalytic capacity does not quantify phosphate supply in vivo; Pi denotes pH-dependent protonation states. [roberts2004] Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities (2004). https://pubmed.ncbi.nlm.nih.gov/15175005/ DOI: 10.1042/BJ20040511
Complete structured claim and evidence
Human PHOSPHO1 also hydrolyzes phosphocholine, producing inorganic phosphate and choline.
Phosphocholine → Inorganic phosphate (Pi; protonation depends on pH) source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified-enzyme substrate assay
limitations
This reaction uses magnesium-dependent machinery; calcium is the eventual mineral constituent, not the demonstrated phosphatase cofactor.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A second phospholipid-headgroup metabolite can supply phosphate.
primary_references
[roberts2004] Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities (2004). https://pubmed.ncbi.nlm.nih.gov/15175005/ DOI: 10.1042/BJ20040511
tissue_or_cell_type
Recombinant enzyme
Calcium: mechanism-first literature curation (2026-09-17) · lines 908–917
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified-enzyme substrate assay · source_derived_draft · unverified_draft
### phospho1-phosphocholine-hydrolysis Human PHOSPHO1 also hydrolyzes phosphocholine, producing inorganic phosphate and choline. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second phospholipid-headgroup metabolite can supply phosphate. organism: Homo sapiens tissue_or_cell_type: Recombinant enzyme experimental_model: Purified-enzyme substrate assay limitations: This reaction uses magnesium-dependent machinery; calcium is the eventual mineral constituent, not the demonstrated phosphatase cofactor. [roberts2004] Human PHOSPHO1 exhibits high specific phosphoethanolamine and phosphocholine phosphatase activities (2004). https://pubmed.ncbi.nlm.nih.gov/15175005/ DOI: 10.1042/BJ20040511
Complete structured claim and evidence
Active PHOSPHO1 was detected inside osteoblast-derived matrix vesicles; phosphoethanolamine hydrolase activity became accessible after vesicle sonication.
Phosphoethanolamine/phosphocholine phosphatase PHOSPHO1 → Mineralizing matrix vesicle source_derived_draftungraded
Experimental context and source evidence
compartment_description
Matrix-vesicle lumen
experimental_model
Localization and activity assays, including Alpl-deficient vesicles
limitations
Localization does not establish the sole route for vesicle phosphate or calcium entry.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Mineralizing vesicles contain phosphate-generating machinery within their membrane.
primary_references
[roberts2007] Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization (2007). https://pubmed.ncbi.nlm.nih.gov/17227223/ DOI: 10.1359/jbmr.070108
tissue_or_cell_type
Osteoblast-derived matrix vesicles
Calcium: mechanism-first literature curation (2026-09-17) · lines 919–929
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Localization and activity assays, including Alpl-deficient vesicles · source_derived_draft · unverified_draft
### phospho1-in-matrix-vesicles Active PHOSPHO1 was detected inside osteoblast-derived matrix vesicles; phosphoethanolamine hydrolase activity became accessible after vesicle sonication. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mineralizing vesicles contain phosphate-generating machinery within their membrane. organism: Mus musculus tissue_or_cell_type: Osteoblast-derived matrix vesicles experimental_model: Localization and activity assays, including Alpl-deficient vesicles limitations: Localization does not establish the sole route for vesicle phosphate or calcium entry. compartment_description: Matrix-vesicle lumen [roberts2007] Functional involvement of PHOSPHO1 in matrix vesicle-mediated skeletal mineralization (2007). https://pubmed.ncbi.nlm.nih.gov/17227223/ DOI: 10.1359/jbmr.070108
Complete structured claim and evidence
ALPL/TNAP hydrolyzes extracellular pyrophosphate to inorganic phosphate, reducing an inhibitor of matrix mineralization.
Inorganic pyrophosphate → Inorganic phosphate (Pi; protonation depends on pH) source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular matrix and vesicle surface
experimental_model
Genetic and ex vivo pyrophosphate/mineralization experiments
limitations
Pi and PPi labels pool protonation states; this is not evidence that calcium activates TNAP.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
TNAP removes a local brake on calcium phosphate crystal growth.
primary_references
[hessle2002] Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization (2002). https://pmc.ncbi.nlm.nih.gov/articles/PMC123160/ DOI: 10.1073/pnas.142063399
tissue_or_cell_type
Osteoblast matrix and matrix vesicles
Calcium: mechanism-first literature curation (2026-09-17) · lines 931–941
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetic and ex vivo pyrophosphate/mineralization experiments · source_derived_draft · unverified_draft
### alpl-pyrophosphate-hydrolysis ALPL/TNAP hydrolyzes extracellular pyrophosphate to inorganic phosphate, reducing an inhibitor of matrix mineralization. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: TNAP removes a local brake on calcium phosphate crystal growth. organism: Mus musculus tissue_or_cell_type: Osteoblast matrix and matrix vesicles experimental_model: Genetic and ex vivo pyrophosphate/mineralization experiments limitations: Pi and PPi labels pool protonation states; this is not evidence that calcium activates TNAP. compartment_description: Extracellular matrix and vesicle surface [hessle2002] Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization (2002). https://pmc.ncbi.nlm.nih.gov/articles/PMC123160/ DOI: 10.1073/pnas.142063399
Complete structured claim and evidence
In Alpl-deficient mice and osteoblast preparations, excess pyrophosphate accompanied poor mineralization; removing Enpp1 normalized pyrophosphate and improved mineral deposition.
Inorganic pyrophosphate → Skeletal matrix mineralization source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Single versus combined Alpl/Enpp1 knockout
limitations
The genetic rescue supports local PPi control; it is not a calcium-supplement experiment.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Mineral formation depends on controlling an inhibitor as well as supplying calcium.
primary_references
[hessle2002] Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization (2002). https://pmc.ncbi.nlm.nih.gov/articles/PMC123160/ DOI: 10.1073/pnas.142063399
tissue_or_cell_type
Bone and cultured osteoblast matrix
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 943–952
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single versus combined Alpl/Enpp1 knockout · source_derived_draft · unverified_draft
### pyrophosphate-restrains-mineral-deposition In Alpl-deficient mice and osteoblast preparations, excess pyrophosphate accompanied poor mineralization; removing Enpp1 normalized pyrophosphate and improved mineral deposition. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mineral formation depends on controlling an inhibitor as well as supplying calcium. organism: Mus musculus tissue_or_cell_type: Bone and cultured osteoblast matrix experimental_model: Single versus combined Alpl/Enpp1 knockout limitations: The genetic rescue supports local PPi control; it is not a calcium-supplement experiment. [hessle2002] Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization (2002). https://pmc.ncbi.nlm.nih.gov/articles/PMC123160/ DOI: 10.1073/pnas.142063399
Complete structured claim and evidence
Combined loss of PHOSPHO1 and ALPL prevented skeletal mineralization in the reported double-null mouse embryos.
Phosphoethanolamine/phosphocholine phosphatase PHOSPHO1 → Tissue-nonspecific alkaline phosphatase ALPL / TNAP source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Phospho1/Alpl double-null embryos
limitations
Severe genetic disruption is not equivalent to low dietary calcium; isolated exceptions and developmental timing matter.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
These phosphate-handling enzymes provide complementary support for mineral formation.
primary_references
[yadav2011] Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification (2011). https://pubmed.ncbi.nlm.nih.gov/20684022/ DOI: 10.1002/jbmr.195
tissue_or_cell_type
Developing skeleton
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 954–963
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phospho1/Alpl double-null embryos · source_derived_draft · unverified_draft
### phospho1-alpl-double-loss-mineralization Combined loss of PHOSPHO1 and ALPL prevented skeletal mineralization in the reported double-null mouse embryos. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: These phosphate-handling enzymes provide complementary support for mineral formation. organism: Mus musculus tissue_or_cell_type: Developing skeleton experimental_model: Phospho1/Alpl double-null embryos limitations: Severe genetic disruption is not equivalent to low dietary calcium; isolated exceptions and developmental timing matter. [yadav2011] Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification (2011). https://pubmed.ncbi.nlm.nih.gov/20684022/ DOI: 10.1002/jbmr.195
Complete structured claim and evidence
Phospho1-null mouse incisors were hypomineralized, with a further defect after loss of one Alpl allele.
Phosphoethanolamine/phosphocholine phosphatase PHOSPHO1 → Dentin mineralization source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Phospho1-null and Phospho1-null/Alpl-heterozygous mice
limitations
A developmental machinery defect; it does not establish dietary calcium deficiency as its cause.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
Tooth dentin depends on mineral-processing enzymes as well as mineral supply.
primary_references
[mckee2013] Compounded PHOSPHO1/ALPL deficiencies reduce dentin mineralization (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3711567/ DOI: 10.1177/0022034513490958
tissue_or_cell_type
Incisor dentin and odontoblast-associated vesicles
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 965–974
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phospho1-null and Phospho1-null/Alpl-heterozygous mice · source_derived_draft · unverified_draft
### phospho1-loss-reduces-dentin-mineralization Phospho1-null mouse incisors were hypomineralized, with a further defect after loss of one Alpl allele. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Tooth dentin depends on mineral-processing enzymes as well as mineral supply. organism: Mus musculus tissue_or_cell_type: Incisor dentin and odontoblast-associated vesicles experimental_model: Phospho1-null and Phospho1-null/Alpl-heterozygous mice limitations: A developmental machinery defect; it does not establish dietary calcium deficiency as its cause. [mckee2013] Compounded PHOSPHO1/ALPL deficiencies reduce dentin mineralization (2013). https://pmc.ncbi.nlm.nih.gov/articles/PMC3711567/ DOI: 10.1177/0022034513490958
Complete structured claim and evidence
Early ANK-dependent changes in cellular and extracellular PPi motivated a proposal that ANK directly exports PPi.
Progressive ankylosis protein homolog ANKH → Inorganic pyrophosphate source_derived_draftungraded
Experimental context and source evidence
compartment_description
Plasma membrane
experimental_model
Ank genetics and cell PPi measurements
limitations
Historical hypothesis, not a current unconditional transport assignment; later ATP/ENPP1 experiments require qualification.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus protein; cultured mammalian cells
plain_language
An older transport explanation was inferred from changes in PPi distribution.
primary_references
[ho2000] Role of the mouse ank gene in control of tissue calcification and arthritis (2000). https://pubmed.ncbi.nlm.nih.gov/10894769/ DOI: 10.1126/science.289.5477.265
tissue_or_cell_type
Joint-calcification context
Calcium: mechanism-first literature curation (2026-09-17) · lines 976–986
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ank genetics and cell PPi measurements · source_derived_draft · unverified_draft
### ankh-historical-direct-ppi-export-hypothesis Early ANK-dependent changes in cellular and extracellular PPi motivated a proposal that ANK directly exports PPi. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An older transport explanation was inferred from changes in PPi distribution. organism: Mus musculus protein; cultured mammalian cells tissue_or_cell_type: Joint-calcification context experimental_model: Ank genetics and cell PPi measurements limitations: Historical hypothesis, not a current unconditional transport assignment; later ATP/ENPP1 experiments require qualification. compartment_description: Plasma membrane [ho2000] Role of the mouse ank gene in control of tissue calcification and arthritis (2000). https://pubmed.ncbi.nlm.nih.gov/10894769/ DOI: 10.1126/science.289.5477.265
Complete structured claim and evidence
Mouse ANK expression increased saturable radiolabeled PPi uptake into Xenopus oocytes.
Progressive ankylosis protein homolog ANKH → Inorganic pyrophosphate source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular medium to oocyte
experimental_model
Heterologous expression and radiotracer uptake
limitations
Influx in this model does not establish physiological PPi efflux; retain alongside later ATP-release results.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus protein in Xenopus laevis oocytes
plain_language
An earlier assay measured movement into an egg cell, not export from human bone cells.
primary_references
[gurley2006] Biochemical and genetic analysis of ANK in arthritis and bone disease (2006). https://pubmed.ncbi.nlm.nih.gov/17186460/ DOI: 10.1086/509881
tissue_or_cell_type
Oocyte plasma membrane
Calcium: mechanism-first literature curation (2026-09-17) · lines 988–998
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Heterologous expression and radiotracer uptake · source_derived_draft · unverified_draft
### ank-dependent-ppi-uptake-oocytes Mouse ANK expression increased saturable radiolabeled PPi uptake into Xenopus oocytes. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An earlier assay measured movement into an egg cell, not export from human bone cells. organism: Mus musculus protein in Xenopus laevis oocytes tissue_or_cell_type: Oocyte plasma membrane experimental_model: Heterologous expression and radiotracer uptake limitations: Influx in this model does not establish physiological PPi efflux; retain alongside later ATP-release results. compartment_description: Extracellular medium to oocyte [gurley2006] Biochemical and genetic analysis of ANK in arthritis and bone disease (2006). https://pubmed.ncbi.nlm.nih.gov/17186460/ DOI: 10.1086/509881
Complete structured claim and evidence
ANKH expression drove ATP release from HEK293 cells even when ENPP1 was absent.
Progressive ankylosis protein homolog ANKH → ATP source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol to extracellular medium
experimental_model
ANKH expression with ENPP1 deletion controls
limitations
Cellular export assay; it does not determine purified ANKH transport stoichiometry in every tissue.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
ANKH can provide extracellular ATP for subsequent PPi production.
primary_references
[szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
tissue_or_cell_type
HEK293 cells
Calcium: mechanism-first literature curation (2026-09-17) · lines 1000–1010
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ANKH expression with ENPP1 deletion controls · source_derived_draft · unverified_draft
### ankh-atp-export ANKH expression drove ATP release from HEK293 cells even when ENPP1 was absent. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ANKH can provide extracellular ATP for subsequent PPi production. organism: Homo sapiens tissue_or_cell_type: HEK293 cells experimental_model: ANKH expression with ENPP1 deletion controls limitations: Cellular export assay; it does not determine purified ANKH transport stoichiometry in every tissue. compartment_description: Cytosol to extracellular medium [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
Complete structured claim and evidence
ENPP1 converts extracellular ATP into AMP and PPi; ANKH-expressing cells lacking ENPP1 released ATP without the accompanying PPi accumulation.
ATP → Inorganic pyrophosphate source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular space
experimental_model
ENPP1-proficient versus deficient cells
limitations
Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
An extracellular enzyme converts exported ATP into a mineralization inhibitor.
primary_references
[szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
tissue_or_cell_type
HEK293 extracellular medium
Calcium: mechanism-first literature curation (2026-09-17) · lines 1012–1022
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · ENPP1-proficient versus deficient cells · source_derived_draft · unverified_draft
### enpp1-atp-to-pyrophosphate ENPP1 converts extracellular ATP into AMP and PPi; ANKH-expressing cells lacking ENPP1 released ATP without the accompanying PPi accumulation. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: An extracellular enzyme converts exported ATP into a mineralization inhibitor. organism: Homo sapiens tissue_or_cell_type: HEK293 extracellular medium experimental_model: ENPP1-proficient versus deficient cells limitations: Other ectonucleotidases compete for ATP; PPi is not synonymous with orthophosphate. compartment_description: Extracellular space [szeri2022] The mineralization regulator ANKH mediates cellular efflux of ATP, not pyrophosphate (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9098669/ DOI: 10.1002/jbmr.4528
Complete structured claim and evidence
ANKH-expressing HEK293 cells released citrate; Ank-mutant mice also had depleted bone-matrix citrate.
Progressive ankylosis protein homolog ANKH → Citrate source_derived_draftungraded
Experimental context and source evidence
compartment_description
Cytosol to extracellular space
experimental_model
Metabolomics and Ank-mutant tissue measurements
limitations
Citrate is a separate substrate; these findings do not prove that citrate alone explains altered bone strength.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens cells; Mus musculus
plain_language
ANKH affects a mineral-associated organic component as well as PPi supply.
primary_references
[szeri2020] The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP (2020). https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008884 DOI: 10.1371/journal.pgen.1008884
tissue_or_cell_type
Cell medium and bone matrix
Calcium: mechanism-first literature curation (2026-09-17) · lines 1024–1034
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolomics and Ank-mutant tissue measurements · source_derived_draft · unverified_draft
### ankh-citrate-export ANKH-expressing HEK293 cells released citrate; Ank-mutant mice also had depleted bone-matrix citrate. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: ANKH affects a mineral-associated organic component as well as PPi supply. organism: Homo sapiens cells; Mus musculus tissue_or_cell_type: Cell medium and bone matrix experimental_model: Metabolomics and Ank-mutant tissue measurements limitations: Citrate is a separate substrate; these findings do not prove that citrate alone explains altered bone strength. compartment_description: Cytosol to extracellular space [szeri2020] The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP (2020). https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008884 DOI: 10.1371/journal.pgen.1008884
Complete structured claim and evidence
Soluble RANKL/ODF supported osteoclast-like-cell formation from mouse spleen precursors in the presence of M-CSF without osteoblast/stromal coculture.
RANK ligand / TNFSF11 → Osteoclast differentiation source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant ligand culture assay
limitations
M-CSF and culture context are required; this is not a calcium-supplement response.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
A bone-cell signal can instruct precursors to become bone-resorbing cells.
primary_references
[yasuda1998] Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19881/ DOI: 10.1073/pnas.95.7.3597
tissue_or_cell_type
Spleen-derived osteoclast precursors
Calcium: mechanism-first literature curation (2026-09-17) · lines 1036–1045
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant ligand culture assay · source_derived_draft · unverified_draft
### rankl-promotes-osteoclast-differentiation Soluble RANKL/ODF supported osteoclast-like-cell formation from mouse spleen precursors in the presence of M-CSF without osteoblast/stromal coculture. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A bone-cell signal can instruct precursors to become bone-resorbing cells. organism: Mus musculus tissue_or_cell_type: Spleen-derived osteoclast precursors experimental_model: Recombinant ligand culture assay limitations: M-CSF and culture context are required; this is not a calcium-supplement response. [yasuda1998] Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19881/ DOI: 10.1073/pnas.95.7.3597
Complete structured claim and evidence
Osteoprotegerin bound RANKL/ODF and blocked its osteoclastogenic activity in the mouse culture system.
Osteoprotegerin / TNFRSF11B / OPG → RANK ligand / TNFSF11 source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular space
experimental_model
Ligand identification and inhibition assays
limitations
The experiment establishes ligand sequestration in this system, not clinical fracture protection.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus cell system
plain_language
OPG can intercept the signal that promotes bone-resorbing cells.
primary_references
[yasuda1998] Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19881/ DOI: 10.1073/pnas.95.7.3597
tissue_or_cell_type
Stromal and osteoclast-precursor cultures
Calcium: mechanism-first literature curation (2026-09-17) · lines 1047–1057
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ligand identification and inhibition assays · source_derived_draft · unverified_draft
### opg-binds-rankl Osteoprotegerin bound RANKL/ODF and blocked its osteoclastogenic activity in the mouse culture system. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: OPG can intercept the signal that promotes bone-resorbing cells. organism: Mus musculus cell system tissue_or_cell_type: Stromal and osteoclast-precursor cultures experimental_model: Ligand identification and inhibition assays limitations: The experiment establishes ligand sequestration in this system, not clinical fracture protection. compartment_description: Extracellular space [yasuda1998] Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL (1998). https://pmc.ncbi.nlm.nih.gov/articles/PMC19881/ DOI: 10.1073/pnas.95.7.3597
Complete structured claim and evidence
Rank-null mice lacked osteoclasts and developed osteopetrosis; marrow transplantation or receptor re-expression restored osteoclast development.
Receptor activator of NF-kappa-B / TNFRSF11A / RANK → Osteoclast differentiation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Rank-null mice and genetic rescue
limitations
Complete receptor loss is a machinery defect, not evidence of nutritional calcium deficiency.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
RANK is necessary for normal formation of bone-resorbing cells in this mouse model.
primary_references
[li2000] RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism (2000). https://pubmed.ncbi.nlm.nih.gov/10677500/ DOI: 10.1073/pnas.97.4.1566
tissue_or_cell_type
Bone and hematopoietic precursors
trigger_kind
machinery_impairment Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 1059–1068
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rank-null mice and genetic rescue · source_derived_draft · unverified_draft
### rank-loss-blocks-osteoclast-formation Rank-null mice lacked osteoclasts and developed osteopetrosis; marrow transplantation or receptor re-expression restored osteoclast development. Condition category: machinery_impairment nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: RANK is necessary for normal formation of bone-resorbing cells in this mouse model. organism: Mus musculus tissue_or_cell_type: Bone and hematopoietic precursors experimental_model: Rank-null mice and genetic rescue limitations: Complete receptor loss is a machinery defect, not evidence of nutritional calcium deficiency. [li2000] RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism (2000). https://pubmed.ncbi.nlm.nih.gov/10677500/ DOI: 10.1073/pnas.97.4.1566
Complete structured claim and evidence
A calcium-deficient diet increased osteoclasts and bone loss in adult mice; osteocyte-directed Rankl deletion blunted the response.
Calcium → Osteoclastic bone resorption source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
30 days of 0.01% versus 0.516% dietary calcium
limitations
Mouse diet and Cre-targeting scope limit human generalization; bone loss was blunted, not necessarily abolished.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus
plain_language
When dietary calcium was severely restricted, osteocyte RANKL helped drive withdrawal from bone.
primary_references
[xiong2014] Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4125539/ DOI: 10.1016/j.bone.2014.06.006
tissue_or_cell_type
Adult cortical and cancellous bone
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 1070–1079
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 30 days of 0.01% versus 0.516% dietary calcium · source_derived_draft · unverified_draft
### low-calcium-diet-osteocyte-rankl-resorption A calcium-deficient diet increased osteoclasts and bone loss in adult mice; osteocyte-directed Rankl deletion blunted the response. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: When dietary calcium was severely restricted, osteocyte RANKL helped drive withdrawal from bone. organism: Mus musculus tissue_or_cell_type: Adult cortical and cancellous bone experimental_model: 30 days of 0.01% versus 0.516% dietary calcium limitations: Mouse diet and Cre-targeting scope limit human generalization; bone loss was blunted, not necessarily abolished. [xiong2014] Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency (2014). https://pmc.ncbi.nlm.nih.gov/articles/PMC4125539/ DOI: 10.1016/j.bone.2014.06.006
Complete structured claim and evidence
Resorbing osteoclasts acidified the extracellular compartment beneath their ruffled border and reacidified it after ammonium chloride washout.
Osteoclast → Acidification of the osteoclast resorption lacuna source_derived_draftungraded
Experimental context and source evidence
compartment_description
Sealed extracellular resorption lacuna
experimental_model
Acridine-orange localization and reversible pH perturbation
limitations
This study localizes acidification; it does not identify a particular modern proton-pump subunit or measure whole-body calcium flux.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Gallus gallus
plain_language
Bone-resorbing cells create a locally acidic space against bone.
primary_references
[baron1985] Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border (1985). https://rupress.org/jcb/article/101/6/2210/21648/Cell-mediated-extracellular-acidification-and-bone DOI: 10.1083/jcb.101.6.2210
tissue_or_cell_type
Osteoclast-bone interface
Calcium: mechanism-first literature curation (2026-09-17) · lines 1081–1091
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acridine-orange localization and reversible pH perturbation · source_derived_draft · unverified_draft
### osteoclast-lacuna-acidification Resorbing osteoclasts acidified the extracellular compartment beneath their ruffled border and reacidified it after ammonium chloride washout. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bone-resorbing cells create a locally acidic space against bone. organism: Gallus gallus tissue_or_cell_type: Osteoclast-bone interface experimental_model: Acridine-orange localization and reversible pH perturbation limitations: This study localizes acidification; it does not identify a particular modern proton-pump subunit or measure whole-body calcium flux. compartment_description: Sealed extracellular resorption lacuna [baron1985] Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border (1985). https://rupress.org/jcb/article/101/6/2210/21648/Cell-mediated-extracellular-acidification-and-bone DOI: 10.1083/jcb.101.6.2210
Complete structured claim and evidence
Daily PTH(1-34) injections reduced osteoblast apoptosis and increased bone formation in the studied adult mouse strains.
Parathyroid hormone / PTH → Osteoblast apoptosis source_derived_draftungraded
Experimental context and source evidence
experimental_model
Daily PTH(1-34) administration and cell assays
limitations
An experimental dosing context; it must not be generalized to sustained endogenous PTH elevation or calcium supplementation.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus; rodent and human cell corroboration
plain_language
Intermittent PTH exposure can prolong the survival of bone-forming cells.
primary_references
[jilka1999] Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone (1999). https://www.jci.org/articles/view/6610 DOI: 10.1172/JCI6610
tissue_or_cell_type
Cancellous bone osteoblasts
Calcium: mechanism-first literature curation (2026-09-17) · lines 1093–1102
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Daily PTH(1-34) administration and cell assays · source_derived_draft · unverified_draft
### intermittent-pth-reduces-osteoblast-apoptosis Daily PTH(1-34) injections reduced osteoblast apoptosis and increased bone formation in the studied adult mouse strains. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Intermittent PTH exposure can prolong the survival of bone-forming cells. organism: Mus musculus; rodent and human cell corroboration tissue_or_cell_type: Cancellous bone osteoblasts experimental_model: Daily PTH(1-34) administration and cell assays limitations: An experimental dosing context; it must not be generalized to sustained endogenous PTH elevation or calcium supplementation. [jilka1999] Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone (1999). https://www.jci.org/articles/view/6610 DOI: 10.1172/JCI6610
Complete structured claim and evidence
In the bovine prothrombin Gla-domain structure, the lysophosphatidylserine headgroup contacted domain-bound Ca2+ and gamma-carboxyglutamate residues.
Calcium ion → Gamma-carboxylated prothrombin Gla domain source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular protein-membrane interface
experimental_model
X-ray crystallography and NMR with lysophosphatidylserine
limitations
The carboxylated Gla domain is a vitamin-K-dependent protein state; calcium binding does not perform gamma-carboxylation.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Bos taurus
plain_language
Protein-bound calcium helps a clotting protein recognize a membrane lipid headgroup.
primary_references
[huang2003] Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins (2003). https://www.nature.com/articles/nsb971 DOI: 10.1038/nsb971
tissue_or_cell_type
Purified prothrombin fragment; blood-protein context
Calcium: mechanism-first literature curation (2026-09-17) · lines 1104–1114
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography and NMR with lysophosphatidylserine · source_derived_draft · unverified_draft
### calcium-gla-phosphatidylserine-binding In the bovine prothrombin Gla-domain structure, the lysophosphatidylserine headgroup contacted domain-bound Ca2+ and gamma-carboxyglutamate residues. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protein-bound calcium helps a clotting protein recognize a membrane lipid headgroup. organism: Bos taurus tissue_or_cell_type: Purified prothrombin fragment; blood-protein context experimental_model: X-ray crystallography and NMR with lysophosphatidylserine limitations: The carboxylated Gla domain is a vitamin-K-dependent protein state; calcium binding does not perform gamma-carboxylation. compartment_description: Extracellular protein-membrane interface [huang2003] Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins (2003). https://www.nature.com/articles/nsb971 DOI: 10.1038/nsb971
Complete structured claim and evidence
Factor Xa activated bovine prothrombin efficiently when factor Va, Ca2+ and phosphatidylserine-containing phospholipids assembled the complete prothrombinase system.
Prothrombin / coagulation factor II / F2 → Thrombin (proteolytically activated F2) source_derived_draftungraded
Experimental context and source evidence
compartment_description
Phospholipid surface
experimental_model
Kinetic reconstitution with defined phospholipids
limitations
Low residual Xa activity exists without the complete complex; this establishes biochemical assistance, not that extra dietary calcium accelerates clotting.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Bos taurus
plain_language
Calcium helps the membrane-associated clotting machinery generate thrombin.
primary_references
[rosing1980] The role of phospholipids and factor Va in the prothrombinase complex (1980). https://pubmed.ncbi.nlm.nih.gov/7350159/ DOI: 10.1016/S0021-9258(19)86294-4
tissue_or_cell_type
Purified blood proteins
Calcium: mechanism-first literature curation (2026-09-17) · lines 1116–1126
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic reconstitution with defined phospholipids · source_derived_draft · unverified_draft
### calcium-phospholipid-prothrombinase Factor Xa activated bovine prothrombin efficiently when factor Va, Ca2+ and phosphatidylserine-containing phospholipids assembled the complete prothrombinase system. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps the membrane-associated clotting machinery generate thrombin. organism: Bos taurus tissue_or_cell_type: Purified blood proteins experimental_model: Kinetic reconstitution with defined phospholipids limitations: Low residual Xa activity exists without the complete complex; this establishes biochemical assistance, not that extra dietary calcium accelerates clotting. compartment_description: Phospholipid surface [rosing1980] The role of phospholipids and factor Va in the prothrombinase complex (1980). https://pubmed.ncbi.nlm.nih.gov/7350159/ DOI: 10.1016/S0021-9258(19)86294-4
Complete structured claim and evidence
Three Ca2+ ions coordinated at the interface of mouse E-cadherin extracellular domains 1 and 2 support their extended, rigid arrangement.
Calcium ion → E-cadherin ectodomain rigidity source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular domain
experimental_model
Two-domain crystal structure
limitations
The crystallized fragment is not a complete living adherens junction; crystal dimer geometry alone does not define every adhesion contact.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus protein
plain_language
Calcium braces the outside portion of a cell-adhesion protein.
primary_references
[nagar1996] Structural basis of calcium-induced E-cadherin rigidification and dimerization (1996). https://pubmed.ncbi.nlm.nih.gov/8598933/ DOI: 10.1038/380360a0
tissue_or_cell_type
Purified E-cadherin ectodomain
Calcium: mechanism-first literature curation (2026-09-17) · lines 1128–1138
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-domain crystal structure · source_derived_draft · unverified_draft
### calcium-rigidifies-e-cadherin Three Ca2+ ions coordinated at the interface of mouse E-cadherin extracellular domains 1 and 2 support their extended, rigid arrangement. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium braces the outside portion of a cell-adhesion protein. organism: Mus musculus protein tissue_or_cell_type: Purified E-cadherin ectodomain experimental_model: Two-domain crystal structure limitations: The crystallized fragment is not a complete living adherens junction; crystal dimer geometry alone does not define every adhesion contact. compartment_description: Extracellular domain [nagar1996] Structural basis of calcium-induced E-cadherin rigidification and dimerization (1996). https://pubmed.ncbi.nlm.nih.gov/8598933/ DOI: 10.1038/380360a0
Complete structured claim and evidence
Calcium binding protected the recombinant mouse E-cadherin ectodomain from tryptic cleavage; calcium depletion caused a reversible conformational change.
Calcium ion → E-cadherin ectodomain proteolysis source_derived_draftungraded
Experimental context and source evidence
compartment_description
Extracellular domain
experimental_model
Calcium titration, electron microscopy and trypsin assay
limitations
In-vitro calcium removal is not dietary calcium deficiency; the soluble fragment did not self-associate under these assay conditions.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Mus musculus protein expressed in insect cells
plain_language
Bound calcium helps keep the adhesion protein folded and resistant to protease attack.
primary_references
[pokutta1994] Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding (1994). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1994.tb19080.x DOI: 10.1111/j.1432-1033.1994.tb19080.x
tissue_or_cell_type
Purified extracellular domain
Calcium: mechanism-first literature curation (2026-09-17) · lines 1140–1150
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Calcium titration, electron microscopy and trypsin assay · source_derived_draft · unverified_draft
### calcium-protects-e-cadherin-from-proteolysis Calcium binding protected the recombinant mouse E-cadherin ectodomain from tryptic cleavage; calcium depletion caused a reversible conformational change. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Bound calcium helps keep the adhesion protein folded and resistant to protease attack. organism: Mus musculus protein expressed in insect cells tissue_or_cell_type: Purified extracellular domain experimental_model: Calcium titration, electron microscopy and trypsin assay limitations: In-vitro calcium removal is not dietary calcium deficiency; the soluble fragment did not self-associate under these assay conditions. compartment_description: Extracellular domain [pokutta1994] Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding (1994). https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1994.tb19080.x DOI: 10.1111/j.1432-1033.1994.tb19080.x
Complete structured claim and evidence
Calcium absorption from the tested spinach meal was lower than from milk at equal calcium load.
Calcium → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
13-adult crossover; 200 mg calcium per test meal, double-isotope measurement.
exposure
Mean fractional absorption: spinach 5.1%, milk 27.6%; oxalate slightly exceeded calcium stoichiometrically in tested spinach.
limitations
Food-matrix comparison; oxalate binding was inferred from composition, not isolated experimentally. Not a comparison of every plant food.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Equal calcium on a food label need not mean equal absorption.
primary_references
[cal-clin-heaney1988] Calcium absorbability from spinach (1988). https://pubmed.ncbi.nlm.nih.gov/3354496/ DOI: 10.1093/ajcn/47.4.707
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1152–1162
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 13-adult crossover; 200 mg calcium per test meal, double-isotope measurement. · source_derived_draft · unverified_draft
### cal-food-spinach-absorption Calcium absorption from the tested spinach meal was lower than from milk at equal calcium load. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Equal calcium on a food label need not mean equal absorption. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 13-adult crossover; 200 mg calcium per test meal, double-isotope measurement. limitations: Food-matrix comparison; oxalate binding was inferred from composition, not isolated experimentally. Not a comparison of every plant food. exposure: Mean fractional absorption: spinach 5.1%, milk 27.6%; oxalate slightly exceeded calcium stoichiometrically in tested spinach. [cal-clin-heaney1988] Calcium absorbability from spinach (1988). https://pubmed.ncbi.nlm.nih.gov/3354496/ DOI: 10.1093/ajcn/47.4.707
Complete structured claim and evidence
Fasting achlorhydric participants absorbed substantially less calcium from carbonate than from citrate.
Calcium carbonate → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
11 achlorhydric patients and nine controls; 250 mg calcium isotope tests.
exposure
Fasting achlorhydric mean fractions: carbonate 0.042, citrate 0.452; normal subjects showed no significant formulation difference.
limitations
Not evidence that carbonate always fails or citrate always outperforms it.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Low stomach acid can change how a calcium preparation is absorbed.
primary_references
[cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1164–1174
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 11 achlorhydric patients and nine controls; 250 mg calcium isotope tests. · source_derived_draft · unverified_draft
### cal-carbonate-fasting-achlorhydria Fasting achlorhydric participants absorbed substantially less calcium from carbonate than from citrate. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low stomach acid can change how a calcium preparation is absorbed. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 11 achlorhydric patients and nine controls; 250 mg calcium isotope tests. limitations: Not evidence that carbonate always fails or citrate always outperforms it. exposure: Fasting achlorhydric mean fractions: carbonate 0.042, citrate 0.452; normal subjects showed no significant formulation difference. [cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202
Complete structured claim and evidence
Calcium carbonate given with a normal breakfast showed normal absorption in the achlorhydric participants.
Calcium carbonate → Intestinal calcium absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
Meal comparison in the achlorhydria absorption study.
limitations
Small study; the meal experiment did not isolate a molecular rescue mechanism.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The meal changed the result seen during fasting.
primary_references
[cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1176–1185
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Meal comparison in the achlorhydria absorption study. · source_derived_draft · unverified_draft
### cal-carbonate-meal-achlorhydria Calcium carbonate given with a normal breakfast showed normal absorption in the achlorhydric participants. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The meal changed the result seen during fasting. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Meal comparison in the achlorhydria absorption study. limitations: Small study; the meal experiment did not isolate a molecular rescue mechanism. [cal-clin-recker1985] Calcium absorption and achlorhydria (1985). https://pubmed.ncbi.nlm.nih.gov/4000241/ DOI: 10.1056/NEJM198507113130202
Complete structured claim and evidence
Calcium-containing treatment produced more biochemical and radiographic healing than vitamin D alone in the Nigerian rickets trial.
Calcium → Nutritional rickets healing source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
123 children, 24-week randomized trial; low calcium intake also present in matched controls.
exposure
1000 mg elemental calcium/day, vitamin D injections, or both. Combined healing endpoint: calcium 61%, combined 58%, vitamin D 19%. Historical regimens only.
limitations
Does not make every case of rickets calcium-deficiency disease. The combined endpoint included alkaline phosphatase and radiographs. The injected vitamin D molecular form is not assigned here.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
In these children, replacing calcium helped heal rickets.
primary_references
[cal-clin-thacher1999] A Comparison of Calcium, Vitamin D, or Both for Nutritional Rickets in Nigerian Children (1999). https://www.nejm.org/doi/full/10.1056/NEJM199908193410803 DOI: 10.1056/NEJM199908193410803
tissue_or_cell_type
Human clinical or absorption endpoint
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 1187–1197
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 123 children, 24-week randomized trial; low calcium intake also present in matched controls. · source_derived_draft · unverified_draft
### cal-rickets-repletion Calcium-containing treatment produced more biochemical and radiographic healing than vitamin D alone in the Nigerian rickets trial. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: In these children, replacing calcium helped heal rickets. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 123 children, 24-week randomized trial; low calcium intake also present in matched controls. limitations: Does not make every case of rickets calcium-deficiency disease. The combined endpoint included alkaline phosphatase and radiographs. The injected vitamin D molecular form is not assigned here. exposure: 1000 mg elemental calcium/day, vitamin D injections, or both. Combined healing endpoint: calcium 61%, combined 58%, vitamin D 19%. Historical regimens only. [cal-clin-thacher1999] A Comparison of Calcium, Vitamin D, or Both for Nutritional Rickets in Nigerian Children (1999). https://www.nejm.org/doi/full/10.1056/NEJM199908193410803 DOI: 10.1056/NEJM199908193410803
Complete structured claim and evidence
Combined calcium and vitamin D lowered hip-fracture occurrence in the elderly-women trial.
Calcium → Hip fracture incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
3270 elderly women; mean age 84; 18-month randomized trial.
exposure
1.2 g elemental calcium as tricalcium phosphate plus 800 IU vitamin D3/day; 43% lower hip-fracture count among completers, with similar direction in intention-to-treat analysis.
limitations
Calcium-specific attribution is impossible because vitamin D was coadministered. Completer and intention-to-treat analyses must be distinguished.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A combined intervention reduced fractures in this older population.
primary_references
[cal-clin-chapuy1992] Vitamin D3 and calcium to prevent hip fractures in elderly women (1992). https://pubmed.ncbi.nlm.nih.gov/1331788/ DOI: 10.1056/NEJM199212033272305
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1199–1209
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 3270 elderly women; mean age 84; 18-month randomized trial. · source_derived_draft · unverified_draft
### cal-chapuy-hip-fractures Combined calcium and vitamin D lowered hip-fracture occurrence in the elderly-women trial. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A combined intervention reduced fractures in this older population. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 3270 elderly women; mean age 84; 18-month randomized trial. limitations: Calcium-specific attribution is impossible because vitamin D was coadministered. Completer and intention-to-treat analyses must be distinguished. exposure: 1.2 g elemental calcium as tricalcium phosphate plus 800 IU vitamin D3/day; 43% lower hip-fracture count among completers, with similar direction in intention-to-treat analysis. [cal-clin-chapuy1992] Vitamin D3 and calcium to prevent hip fractures in elderly women (1992). https://pubmed.ncbi.nlm.nih.gov/1331788/ DOI: 10.1056/NEJM199212033272305
Complete structured claim and evidence
WHI calcium plus vitamin D did not significantly reduce hip fractures in the intention-to-treat analysis.
Calcium → Hip fracture incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
36,282 postmenopausal women; seven-year mean follow-up.
exposure
1000 mg elemental calcium as carbonate plus 400 IU vitamin D3/day; hip-fracture HR 0.88, 95% CI 0.72-1.08.
limitations
Adherence and background supplement use complicate comparison; a nonsignificant result is not proof of zero effect.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A larger trial did not establish a hip-fracture benefit for its overall assigned-treatment groups.
primary_references
[cal-clin-jackson2006] Calcium plus vitamin D supplementation and the risk of fractures (2006). https://pubmed.ncbi.nlm.nih.gov/16481635/ DOI: 10.1056/NEJMoa055218
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1211–1221
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 36,282 postmenopausal women; seven-year mean follow-up. · source_derived_draft · unverified_draft
### cal-whi-hip-fractures WHI calcium plus vitamin D did not significantly reduce hip fractures in the intention-to-treat analysis. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A larger trial did not establish a hip-fracture benefit for its overall assigned-treatment groups. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 36,282 postmenopausal women; seven-year mean follow-up. limitations: Adherence and background supplement use complicate comparison; a nonsignificant result is not proof of zero effect. exposure: 1000 mg elemental calcium as carbonate plus 400 IU vitamin D3/day; hip-fracture HR 0.88, 95% CI 0.72-1.08. [cal-clin-jackson2006] Calcium plus vitamin D supplementation and the risk of fractures (2006). https://pubmed.ncbi.nlm.nih.gov/16481635/ DOI: 10.1056/NEJMoa055218
Complete structured claim and evidence
WHI assigned calcium plus vitamin D increased reported renal-calculus events relative to placebo.
Calcium → Urinary stone incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized WHI safety outcome.
exposure
Renal-calculus HR 1.17, 95% CI 1.02-1.34; same assigned regimen as the fracture analysis.
limitations
Combined intervention; cannot attribute the whole effect to calcium or identify every stone composition.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The same trial recorded more kidney-stone events with the combined supplements.
primary_references
[cal-clin-jackson2006] Calcium plus vitamin D supplementation and the risk of fractures (2006). https://pubmed.ncbi.nlm.nih.gov/16481635/ DOI: 10.1056/NEJMoa055218
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1223–1233
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized WHI safety outcome. · source_derived_draft · unverified_draft
### cal-whi-urinary-stones WHI assigned calcium plus vitamin D increased reported renal-calculus events relative to placebo. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same trial recorded more kidney-stone events with the combined supplements. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Randomized WHI safety outcome. limitations: Combined intervention; cannot attribute the whole effect to calcium or identify every stone composition. exposure: Renal-calculus HR 1.17, 95% CI 1.02-1.34; same assigned regimen as the fracture analysis. [cal-clin-jackson2006] Calcium plus vitamin D supplementation and the risk of fractures (2006). https://pubmed.ncbi.nlm.nih.gov/16481635/ DOI: 10.1056/NEJMoa055218
Complete structured claim and evidence
A normal-calcium diet with less animal protein and salt reduced stone recurrence compared with a low-calcium diet.
Calcium → Calcium oxalate stone recurrence source_derived_draftungraded
Experimental context and source evidence
experimental_model
120 hypercalciuric male recurrent stone formers; five-year randomized comparison.
exposure
Recurrences 12/60 versus 23/60; RR 0.49, 95% CI 0.24-0.98. Calcium 30 versus 10 mmol/day; intervention also reduced animal protein and salt.
limitations
Multiple dietary components changed together, preventing isolated calcium attribution.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Restricting calcium was not the better strategy in this particular dietary trial.
primary_references
[cal-clin-borghi2002] Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria (2002). https://pubmed.ncbi.nlm.nih.gov/11784873/ DOI: 10.1056/NEJMoa010369
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1235–1245
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 120 hypercalciuric male recurrent stone formers; five-year randomized comparison. · source_derived_draft · unverified_draft
### cal-borghi-stone-recurrence A normal-calcium diet with less animal protein and salt reduced stone recurrence compared with a low-calcium diet. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restricting calcium was not the better strategy in this particular dietary trial. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 120 hypercalciuric male recurrent stone formers; five-year randomized comparison. limitations: Multiple dietary components changed together, preventing isolated calcium attribution. exposure: Recurrences 12/60 versus 23/60; RR 0.49, 95% CI 0.24-0.98. Calcium 30 versus 10 mmol/day; intervention also reduced animal protein and salt. [cal-clin-borghi2002] Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria (2002). https://pubmed.ncbi.nlm.nih.gov/11784873/ DOI: 10.1056/NEJMoa010369
Complete structured claim and evidence
Urinary oxalate rose with the low-calcium diet but fell with the normal-calcium, lower-protein, lower-salt diet.
Calcium → Urinary oxalate excretion source_derived_draftungraded
Experimental context and source evidence
experimental_model
Same randomized dietary trial.
limitations
Urine result supports a plausible intestinal explanation but does not isolate binding or prove mediation of recurrence.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Diet composition changed urinary oxalate as well as calcium.
primary_references
[cal-clin-borghi2002] Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria (2002). https://pubmed.ncbi.nlm.nih.gov/11784873/ DOI: 10.1056/NEJMoa010369
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1247–1256
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same randomized dietary trial. · source_derived_draft · unverified_draft
### cal-borghi-urinary-oxalate Urinary oxalate rose with the low-calcium diet but fell with the normal-calcium, lower-protein, lower-salt diet. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Diet composition changed urinary oxalate as well as calcium. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Same randomized dietary trial. limitations: Urine result supports a plausible intestinal explanation but does not isolate binding or prove mediation of recurrence. [cal-clin-borghi2002] Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria (2002). https://pubmed.ncbi.nlm.nih.gov/11784873/ DOI: 10.1056/NEJMoa010369
Complete structured claim and evidence
Calcium carbonate with meals lowered urinary oxalate from baseline; bedtime dosing did not.
Calcium carbonate → Urinary oxalate excretion source_derived_draftungraded
Experimental context and source evidence
experimental_model
32 healthy men, one-week crossover regimens.
exposure
1 g calcium carbonate with each of three meals versus 3 g carbonate at bedtime: compound mass, not 3 g elemental calcium.
limitations
This experiment measured urine, not long-term stone incidence.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Taking the tested preparation with food changed oxalate handling.
primary_references
[cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1258–1268
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 32 healthy men, one-week crossover regimens. · source_derived_draft · unverified_draft
### cal-meal-urinary-oxalate Calcium carbonate with meals lowered urinary oxalate from baseline; bedtime dosing did not. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Taking the tested preparation with food changed oxalate handling. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 32 healthy men, one-week crossover regimens. limitations: This experiment measured urine, not long-term stone incidence. exposure: 1 g calcium carbonate with each of three meals versus 3 g carbonate at bedtime: compound mass, not 3 g elemental calcium. [cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x
Complete structured claim and evidence
Urinary calcium-oxalate activity product increased after bedtime calcium carbonate but not after meal dosing.
Calcium carbonate → Urinary calcium oxalate activity product source_derived_draftungraded
Experimental context and source evidence
experimental_model
Same short crossover experiment.
limitations
A saturation-related proxy is not an observed kidney-stone event or a universal prediction.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The urinary crystallization proxy depended on timing.
primary_references
[cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1270–1279
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same short crossover experiment. · source_derived_draft · unverified_draft
### cal-bedtime-activity-product Urinary calcium-oxalate activity product increased after bedtime calcium carbonate but not after meal dosing. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The urinary crystallization proxy depended on timing. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Same short crossover experiment. limitations: A saturation-related proxy is not an observed kidney-stone event or a universal prediction. [cal-clin-domrong2004] Schedule of taking calcium supplement and the risk of nephrolithiasis (2004). https://pubmed.ncbi.nlm.nih.gov/15086924/ DOI: 10.1111/j.1523-1755.2004.00587.x
Complete structured claim and evidence
An older-women calcium trial showed an upward myocardial-infarction signal that weakened when registry events were added.
Calcium → Myocardial infarction incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
1471 postmenopausal women, five-year randomized trial; secondary cardiovascular analysis.
exposure
Calcium citrate tablets versus placebo in the parent randomized trial; calcium-only intervention, not the WHI calcium-plus-vitamin-D regimen.
limitations
Adjudicated reported MI RR 2.12 (1.01-4.47); including unreported registry events RR 1.49 (0.86-2.57). Does not establish vascular calcification as the mediator.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The heart-event result depended partly on how events were collected.
primary_references
[cal-clin-bolland2008] Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18198394/ DOI: 10.1136/bmj.39440.525752.BE
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1281–1291
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 1471 postmenopausal women, five-year randomized trial; secondary cardiovascular analysis. · source_derived_draft · unverified_draft
### cal-bolland-myocardial-events An older-women calcium trial showed an upward myocardial-infarction signal that weakened when registry events were added. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The heart-event result depended partly on how events were collected. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 1471 postmenopausal women, five-year randomized trial; secondary cardiovascular analysis. limitations: Adjudicated reported MI RR 2.12 (1.01-4.47); including unreported registry events RR 1.49 (0.86-2.57). Does not establish vascular calcification as the mediator. exposure: Calcium citrate tablets versus placebo in the parent randomized trial; calcium-only intervention, not the WHI calcium-plus-vitamin-D regimen. [cal-clin-bolland2008] Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18198394/ DOI: 10.1136/bmj.39440.525752.BE
Complete structured claim and evidence
WHI found no significant effect of calcium plus vitamin D on myocardial infarction or coronary death.
Calcium → Myocardial infarction or coronary death source_derived_draftungraded
Experimental context and source evidence
experimental_model
Prespecified secondary WHI outcome; seven years.
exposure
MI/coronary-death HR 1.04, 95% CI 0.92-1.18.
limitations
Different cointervention, participants and ascertainment from the calcium-only trial; absence of significance does not prove universal safety.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
This trial did not reproduce a clear increase in coronary events.
primary_references
[cal-clin-hsia2007] Calcium/vitamin D supplementation and cardiovascular events (2007). https://pubmed.ncbi.nlm.nih.gov/17309935/ DOI: 10.1161/CIRCULATIONAHA.106.673491
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1293–1303
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prespecified secondary WHI outcome; seven years. · source_derived_draft · unverified_draft
### cal-whi-coronary-events WHI found no significant effect of calcium plus vitamin D on myocardial infarction or coronary death. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: This trial did not reproduce a clear increase in coronary events. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Prespecified secondary WHI outcome; seven years. limitations: Different cointervention, participants and ascertainment from the calcium-only trial; absence of significance does not prove universal safety. exposure: MI/coronary-death HR 1.04, 95% CI 0.92-1.18. [cal-clin-hsia2007] Calcium/vitamin D supplementation and cardiovascular events (2007). https://pubmed.ncbi.nlm.nih.gov/17309935/ DOI: 10.1161/CIRCULATIONAHA.106.673491
Complete structured claim and evidence
Calcium carbonate reduced recurrent adenomas in the 1999 prevention trial.
Calcium carbonate → Colorectal adenoma recurrence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized post-polypectomy surveillance; 832 participants completed both examinations.
exposure
Adjusted RR 0.81 (95% CI 0.67-0.99) between first and second surveillance examinations.
limitations
Adenoma recurrence is distinct from colorectal-cancer incidence or mortality.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
One trial found fewer recurring colorectal polyps.
primary_references
[cal-clin-baron1999] Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group (1999). https://pubmed.ncbi.nlm.nih.gov/9887161/ DOI: 10.1056/NEJM199901143400204
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1305–1315
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized post-polypectomy surveillance; 832 participants completed both examinations. · source_derived_draft · unverified_draft
### cal-baron1999-adenomas Calcium carbonate reduced recurrent adenomas in the 1999 prevention trial. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: One trial found fewer recurring colorectal polyps. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Randomized post-polypectomy surveillance; 832 participants completed both examinations. limitations: Adenoma recurrence is distinct from colorectal-cancer incidence or mortality. exposure: Adjusted RR 0.81 (95% CI 0.67-0.99) between first and second surveillance examinations. [cal-clin-baron1999] Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group (1999). https://pubmed.ncbi.nlm.nih.gov/9887161/ DOI: 10.1056/NEJM199901143400204
Complete structured claim and evidence
The 2015 trial found no significant reduction in recurrent adenomas with assigned calcium.
Calcium carbonate → Colorectal adenoma recurrence source_derived_draftungraded
Experimental context and source evidence
experimental_model
2259 participants randomized in partial factorial design, 3-5-year follow-up.
exposure
1200 mg calcium/day; calcium versus no-calcium adjusted RR 0.95 (95% CI 0.85-1.06).
limitations
Trial contexts differ; mechanism of between-trial disagreement remains unproven.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A later trial did not confirm the earlier polyp benefit.
primary_references
[cal-clin-baron2015] A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas (2015). https://pubmed.ncbi.nlm.nih.gov/26465985/ DOI: 10.1056/NEJMoa1500409
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1317–1327
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 2259 participants randomized in partial factorial design, 3-5-year follow-up. · source_derived_draft · unverified_draft
### cal-baron2015-adenomas The 2015 trial found no significant reduction in recurrent adenomas with assigned calcium. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A later trial did not confirm the earlier polyp benefit. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 2259 participants randomized in partial factorial design, 3-5-year follow-up. limitations: Trial contexts differ; mechanism of between-trial disagreement remains unproven. exposure: 1200 mg calcium/day; calcium versus no-calcium adjusted RR 0.95 (95% CI 0.85-1.06). [cal-clin-baron2015] A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas (2015). https://pubmed.ncbi.nlm.nih.gov/26465985/ DOI: 10.1056/NEJMoa1500409
Complete structured claim and evidence
In the WHO low-intake pregnancy trial, calcium did not significantly reduce overall preeclampsia incidence.
Calcium → Preeclampsia incidence source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
8325 nulliparous women; blinded placebo comparison.
exposure
1.5 g calcium/day starting before 20 weeks; preeclampsia 4.1% versus 4.5%.
limitations
Preeclampsia was primary; reported benefits on severe outcomes were secondary.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Low baseline intake did not guarantee a benefit on the primary pregnancy outcome.
primary_references
[cal-clin-villar2006] World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women (2006). https://pubmed.ncbi.nlm.nih.gov/16522392/ DOI: 10.1016/j.ajog.2006.01.068
tissue_or_cell_type
Human clinical or absorption endpoint
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 1329–1339
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 8325 nulliparous women; blinded placebo comparison. · source_derived_draft · unverified_draft
### cal-who-preeclampsia In the WHO low-intake pregnancy trial, calcium did not significantly reduce overall preeclampsia incidence. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Low baseline intake did not guarantee a benefit on the primary pregnancy outcome. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 8325 nulliparous women; blinded placebo comparison. limitations: Preeclampsia was primary; reported benefits on severe outcomes were secondary. exposure: 1.5 g calcium/day starting before 20 weeks; preeclampsia 4.1% versus 4.5%. [cal-clin-villar2006] World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women (2006). https://pubmed.ncbi.nlm.nih.gov/16522392/ DOI: 10.1016/j.ajog.2006.01.068
Complete structured claim and evidence
Eclampsia was less frequent with calcium in a secondary analysis of the same WHO trial.
Calcium → Eclampsia incidence source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Same randomized pregnancy trial.
exposure
Eclampsia RR 0.68, 95% CI 0.48-0.97.
limitations
Secondary endpoint; distinct from preeclampsia incidence and not proof of an identified molecular mediator.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A severe secondary outcome improved despite the null primary result.
primary_references
[cal-clin-villar2006] World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women (2006). https://pubmed.ncbi.nlm.nih.gov/16522392/ DOI: 10.1016/j.ajog.2006.01.068
tissue_or_cell_type
Human clinical or absorption endpoint
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Calcium: mechanism-first literature curation (2026-09-17) · lines 1341–1351
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Same randomized pregnancy trial. · source_derived_draft · unverified_draft
### cal-who-eclampsia Eclampsia was less frequent with calcium in a secondary analysis of the same WHO trial. Condition category: nutrient_deficiency nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A severe secondary outcome improved despite the null primary result. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Same randomized pregnancy trial. limitations: Secondary endpoint; distinct from preeclampsia incidence and not proof of an identified molecular mediator. exposure: Eclampsia RR 0.68, 95% CI 0.48-0.97. [cal-clin-villar2006] World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women (2006). https://pubmed.ncbi.nlm.nih.gov/16522392/ DOI: 10.1016/j.ajog.2006.01.068
Complete structured claim and evidence
The 500-mg calcium regimen met the prespecified noninferiority criterion versus 1500 mg for preeclampsia in both 2024 trials.
Calcium → Preeclampsia incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Independent India and Tanzania trials; 11,000 nulliparous women each.
exposure
500 versus 1500 mg elemental calcium/day; preeclampsia RR noninferiority margin 1.54.
limitations
No placebo arm: this cannot establish benefit versus no supplement. Noninferiority is not exact equality or a dosing recommendation.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The lower tested dose performed within the trial margin relative to the higher dose.
primary_references
[cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1353–1363
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Independent India and Tanzania trials; 11,000 nulliparous women each. · source_derived_draft · unverified_draft
### cal-pregnancy-dose-noninferiority The 500-mg calcium regimen met the prespecified noninferiority criterion versus 1500 mg for preeclampsia in both 2024 trials. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The lower tested dose performed within the trial margin relative to the higher dose. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Independent India and Tanzania trials; 11,000 nulliparous women each. limitations: No placebo arm: this cannot establish benefit versus no supplement. Noninferiority is not exact equality or a dosing recommendation. exposure: 500 versus 1500 mg elemental calcium/day; preeclampsia RR noninferiority margin 1.54. [cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
Complete structured claim and evidence
The lower calcium regimen met the preterm-live-birth noninferiority criterion in India.
Calcium → Preterm live birth source_derived_draftungraded
Experimental context and source evidence
experimental_model
India component of the two trials.
exposure
RR 0.89, 95% CI 0.80-0.98; margin 1.16.
limitations
No untreated control; noninferiority need not generalize to another setting.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The India result met the planned comparison threshold.
primary_references
[cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1365–1375
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · India component of the two trials. · source_derived_draft · unverified_draft
### cal-pregnancy-india-preterm The lower calcium regimen met the preterm-live-birth noninferiority criterion in India. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The India result met the planned comparison threshold. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: India component of the two trials. limitations: No untreated control; noninferiority need not generalize to another setting. exposure: RR 0.89, 95% CI 0.80-0.98; margin 1.16. [cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
Complete structured claim and evidence
The lower regimen did not meet preterm-live-birth noninferiority in Tanzania.
Calcium → Preterm live birth source_derived_draftungraded
Experimental context and source evidence
experimental_model
Tanzania component of the two trials.
exposure
RR 1.07, 95% CI 0.95-1.21; margin 1.16.
limitations
Failure to establish noninferiority does not prove inferiority or harm.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The Tanzania estimate was too uncertain to meet the same threshold.
primary_references
[cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1377–1387
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tanzania component of the two trials. · source_derived_draft · unverified_draft
### cal-pregnancy-tanzania-preterm The lower regimen did not meet preterm-live-birth noninferiority in Tanzania. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The Tanzania estimate was too uncertain to meet the same threshold. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Tanzania component of the two trials. limitations: Failure to establish noninferiority does not prove inferiority or harm. exposure: RR 1.07, 95% CI 0.95-1.21; margin 1.16. [cal-clin-dwarkanath2024] Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy (2024). https://www.nejm.org/doi/full/10.1056/NEJMoa2307212 DOI: 10.1056/NEJMoa2307212
Complete structured claim and evidence
Thyroxine adsorbed to calcium carbonate under acidic in-vitro conditions.
Calcium carbonate → T4 source_derived_draftungraded
Experimental context and source evidence
experimental_model
In-vitro adsorption arm accompanying a 20-patient study.
limitations
Supports an absorption-interference mechanism; does not show a systemic blockade of deiodinases.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
A calcium preparation can bind a thyroid medicine before absorption.
primary_references
[cal-clin-singh2000] Effect of calcium carbonate on the absorption of levothyroxine (2000). https://pubmed.ncbi.nlm.nih.gov/10838651/ DOI: 10.1001/jama.283.21.2822
tissue_or_cell_type
Cell-free acidic solution
Calcium: mechanism-first literature curation (2026-09-17) · lines 1389–1398
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In-vitro adsorption arm accompanying a 20-patient study. · source_derived_draft · unverified_draft
### cal-carbonate-thyroxine-adsorption Thyroxine adsorbed to calcium carbonate under acidic in-vitro conditions. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: A calcium preparation can bind a thyroid medicine before absorption. organism: Homo sapiens tissue_or_cell_type: Cell-free acidic solution experimental_model: In-vitro adsorption arm accompanying a 20-patient study. limitations: Supports an absorption-interference mechanism; does not show a systemic blockade of deiodinases. [cal-clin-singh2000] Effect of calcium carbonate on the absorption of levothyroxine (2000). https://pubmed.ncbi.nlm.nih.gov/10838651/ DOI: 10.1001/jama.283.21.2822
Complete structured claim and evidence
Simultaneous calcium carbonate reduced measured levothyroxine absorption in a seven-volunteer experiment.
Calcium carbonate → Levothyroxine absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
Two visits separated by four weeks; serum-based pharmacokinetic estimation.
exposure
1000 micrograms levothyroxine with or without 2 g elemental calcium as carbonate; six-hour total absorption differed (P=0.02).
limitations
Small acute high-dose experiment, not individualized medicine instructions.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The tested calcium preparation reduced the medicine reaching circulation.
primary_references
[cal-clin-singh2001] The acute effect of calcium carbonate on the intestinal absorption of levothyroxine (2001). https://pubmed.ncbi.nlm.nih.gov/11716045/ DOI: 10.1089/105072501753211046
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1400–1410
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two visits separated by four weeks; serum-based pharmacokinetic estimation. · source_derived_draft · unverified_draft
### cal-carbonate-levothyroxine-absorption Simultaneous calcium carbonate reduced measured levothyroxine absorption in a seven-volunteer experiment. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tested calcium preparation reduced the medicine reaching circulation. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Two visits separated by four weeks; serum-based pharmacokinetic estimation. limitations: Small acute high-dose experiment, not individualized medicine instructions. exposure: 1000 micrograms levothyroxine with or without 2 g elemental calcium as carbonate; six-hour total absorption differed (P=0.02). [cal-clin-singh2001] The acute effect of calcium carbonate on the intestinal absorption of levothyroxine (2001). https://pubmed.ncbi.nlm.nih.gov/11716045/ DOI: 10.1089/105072501753211046
Complete structured claim and evidence
Added calcium reduced nonheme-iron absorption in the studied meals.
Calcium → Nonheme iron absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human isotope meal experiments.
limitations
Meal processing/phytate and direct effects both occurred; no specific molecular transporter was identified and long-term iron deficiency was not demonstrated.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
Calcium can reduce iron absorbed from a particular meal.
primary_references
[cal-clin-hallberg1991] Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans (1991). https://pubmed.ncbi.nlm.nih.gov/1984335/ DOI: 10.1093/ajcn/53.1.112
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1412–1421
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human isotope meal experiments. · source_derived_draft · unverified_draft
### cal-meal-nonheme-iron Added calcium reduced nonheme-iron absorption in the studied meals. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium can reduce iron absorbed from a particular meal. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Human isotope meal experiments. limitations: Meal processing/phytate and direct effects both occurred; no specific molecular transporter was identified and long-term iron deficiency was not demonstrated. [cal-clin-hallberg1991] Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans (1991). https://pubmed.ncbi.nlm.nih.gov/1984335/ DOI: 10.1093/ajcn/53.1.112
Complete structured claim and evidence
Calcium also reduced heme-iron absorption in the meal experiments.
Calcium → Heme iron absorption source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human isotope meal experiments with heme substrate.
limitations
A shared mucosal mechanism was proposed, not directly localized to a named protein.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
The acute interaction was not limited to nonheme iron.
primary_references
[cal-clin-hallberg1991] Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans (1991). https://pubmed.ncbi.nlm.nih.gov/1984335/ DOI: 10.1093/ajcn/53.1.112
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1423–1432
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human isotope meal experiments with heme substrate. · source_derived_draft · unverified_draft
### cal-meal-heme-iron Calcium also reduced heme-iron absorption in the meal experiments. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: The acute interaction was not limited to nonheme iron. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: Human isotope meal experiments with heme substrate. limitations: A shared mucosal mechanism was proposed, not directly localized to a named protein. [cal-clin-hallberg1991] Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans (1991). https://pubmed.ncbi.nlm.nih.gov/1984335/ DOI: 10.1093/ajcn/53.1.112
Complete structured claim and evidence
One year of calcium supplementation did not significantly alter measured iron-status markers in adolescent girls.
Calcium → Blood iron-status markers source_derived_draftungraded
Experimental context and source evidence
experimental_model
113 girls, randomized double-blind placebo-controlled trial.
exposure
500 mg calcium/day with evening meal for one year; reported marker comparisons were nonsignificant.
limitations
Does not establish absence of effect in iron-deficient people; hemoglobin, ferritin and soluble transferrin receptor are distinct endpoints.
nutrient_topic
Calcium research collection; topical membership is not evidence of a direct dietary effect. · Calcium
organism
Homo sapiens
plain_language
No significant worsening of iron markers was found after a year of supplementation in these girls.
primary_references
[cal-clin-molgaard2005] Long-term calcium supplementation does not affect the iron status of 12-14-y-old girls (2005). https://pubmed.ncbi.nlm.nih.gov/16002806/ DOI: 10.1093/ajcn.82.1.98
tissue_or_cell_type
Human clinical or absorption endpoint
Calcium: mechanism-first literature curation (2026-09-17) · lines 1434–1444
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 113 girls, randomized double-blind placebo-controlled trial. · source_derived_draft · unverified_draft
### cal-iron-status-longterm One year of calcium supplementation did not significantly alter measured iron-status markers in adolescent girls. Condition category: normal nutrient_topic: Calcium research collection; topical membership is not evidence of a direct dietary effect. plain_language: No significant worsening of iron markers was found after a year of supplementation in these girls. organism: Homo sapiens tissue_or_cell_type: Human clinical or absorption endpoint experimental_model: 113 girls, randomized double-blind placebo-controlled trial. limitations: Does not establish absence of effect in iron-deficient people; hemoglobin, ferritin and soluble transferrin receptor are distinct endpoints. exposure: 500 mg calcium/day with evening meal for one year; reported marker comparisons were nonsignificant. [cal-clin-molgaard2005] Long-term calcium supplementation does not affect the iron status of 12-14-y-old girls (2005). https://pubmed.ncbi.nlm.nih.gov/16002806/ DOI: 10.1093/ajcn.82.1.98
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

A faulty sensor can raise blood calcium.

Condition: machinery_impairment · Inactivating CASR variants

Normal role: Sense extracellular calcium

Recorded consequence: Elevated calcium set point

Scope: Human inherited disease

An oversensitive sensor can lower blood calcium.

Condition: machinery_impairment · CaSR E128A gain of function

Normal role: Set extracellular calcium response

Recorded consequence: Hypocalcemia

Scope: Studied family

Hormonal support helps activate vitamin D during calcium restriction.

Condition: machinery_impairment · Thyroparathyroidectomy during low calcium intake

Normal role: Support calcitriol production

Recorded consequence: Reduced calcitriol production

Scope: Rat surgery/replacement experiment

Vitamin D receptor failure disrupts calcium regulation.

Condition: machinery_impairment · VDR DNA-binding-domain disruption

Normal role: Transmit vitamin D signals

Recorded consequence: Hypocalcemia and compensatory PTH rise

Scope: Developing mice

Dietary mineral delivery can bypass part of receptor failure.

Condition: machinery_impairment · VDR deletion plus rescue diet

Normal role: Supply absorbable calcium

Recorded consequence: Normalized ionized calcium

Scope: Mouse feeding experiment

TRPV6 materially supports calcium uptake in this model.

Condition: machinery_impairment · Trpv6 deletion

Normal role: Support calcium entry

Recorded consequence: Reduced intestinal absorption

Scope: Specified knockout model

Other routes can support active calcium absorption.

Condition: machinery_impairment · Combined Trpv6 and calbindin-D9k deletion

Normal role: Contribute to transcellular transport

Recorded consequence: Residual inducible transport

Scope: Mouse duodenal assays

The measured defect was segment specific.

Condition: machinery_impairment · Cldn2/Cldn12 double deletion

Normal role: Enable paracellular calcium passage

Recorded consequence: Reduced colonic permeability

Scope: Mouse epithelia

The two claudins provide complementary renal retention.

Condition: machinery_impairment · Combined claudin loss

Normal role: Retain filtered calcium

Recorded consequence: Greater urinary loss

Scope: Mouse comparison

Hormonal compensation cannot replace the missing channel.

Condition: machinery_impairment · Trpv5 deletion

Normal role: Reabsorb filtered calcium

Recorded consequence: Renal calcium wasting

Scope: Mouse distal nephron

Gut uptake compensates for kidney losses.

Condition: machinery_impairment · Trpv5 deletion

Normal role: Conserve calcium renally

Recorded consequence: Increased intestinal uptake

Scope: Mouse tracer assay

Inherited junction defects can waste calcium.

Condition: machinery_impairment · Biallelic CLDN19 variants

Normal role: Support renal mineral retention

Recorded consequence: Renal calcium/magnesium wasting

Scope: Affected families

A calcium pump is needed for this hormone response.

Condition: machinery_impairment · Intestinal Atp2b1 deletion

Normal role: Support epithelial calcium export

Recorded consequence: Lost calcitriol-stimulated transport increment

Scope: Mouse villin-Cre model

Low intake recruits a hormonal response.

Condition: nutrient_deficiency · 2000-to-300 mg/day diet change

Normal role: Provide dietary calcium

Recorded consequence: PTH increased

Scope: Nine healthy women

The retained fraction adapts to low intake.

Condition: nutrient_deficiency · 300 mg/day intake

Normal role: Supply calcium

Recorded consequence: Fractional retention increased

Scope: Eight-week restriction

Total and ionized calcium are different measurements.

Condition: biomarker_context · Using total calcium to classify ionized calcium

Normal role: Regulate available extracellular calcium

Recorded consequence: Misclassification risk

Scope: Stage 3-5 CKD

Calculated correction is not a direct ionized-calcium test.

Condition: biomarker_context · Applying albumin-adjustment formulas

Normal role: Reflect circulating calcium

Recorded consequence: Hypocalcemia can be missed and hypercalcemia overcalled

Scope: Alberta laboratory cohort

Normal blood calcium can coexist with inadequate skeletal supply.

Condition: biomarker_context · Intestinal Vdr deletion

Normal role: Maintain extracellular calcium while supplying bone

Recorded consequence: Serum calcium preserved at skeletal expense

Scope: Growing mice

Reducing STIM1 weakens calcium entry after stores empty.

Condition: machinery_impairment · Experimental STIM1 knockdown

Normal role: STIM1 couples ER calcium-store depletion to influx.

Recorded consequence: Reduced store-operated calcium influx

Scope: Homo sapiens; HeLa cells

This inherited channel defect interrupts calcium entry into T cells.

Condition: machinery_impairment · Homozygous ORAI1 R91W mutation

Normal role: ORAI1 conducts calcium after store depletion.

Recorded consequence: Loss of CRAC current and store-operated influx

Scope: Homo sapiens; Patient T lymphocytes

Removing MCU prevents rapid calcium uptake without necessarily collapsing the mitochondrion.

Condition: machinery_impairment · Experimental MCU silencing

Normal role: MCU conducts calcium into the matrix.

Recorded consequence: Markedly impaired mitochondrial calcium uptake

Scope: Homo sapiens and Mus musculus; Cultured cells and mouse liver

Loss of MICU1 can let mitochondria accumulate too much calcium at rest.

Condition: machinery_impairment · Experimental MICU1 depletion

Normal role: MICU1 restrains basal uniporter uptake.

Recorded consequence: Elevated basal mitochondrial matrix calcium

Scope: Homo sapiens; HeLa and endothelial cells

Changing the calcium sensor changes the calcium needed to trigger release.

Condition: machinery_impairment · Engineered reduction of SYT1 calcium affinity

Normal role: SYT1 couples calcium binding to evoked vesicle release.

Recorded consequence: Reduced calcium sensitivity of evoked release

Scope: Mus musculus; Cultured neurons

Removing cyclophilin D protects these cells against calcium-overload injury.

Condition: machinery_impairment · Ppif gene deletion during experimental calcium overload

Normal role: Cyclophilin D sensitizes the permeability-transition response.

Recorded consequence: Reduced susceptibility to calcium-overload-induced death

Scope: Mus musculus; Primary hepatocytes and fibroblasts

Mineral formation depends on controlling an inhibitor as well as supplying calcium.

Condition: machinery_impairment · Alpl deletion with or without Enpp1 deletion.

Normal role: Calcium enters regulated mineral deposition.

Recorded consequence: Excess PPi and hypomineralization were corrected together.

Scope: Mouse genetic interaction.

These phosphate-handling enzymes provide complementary support for mineral formation.

Condition: machinery_impairment · Both phosphatases absent.

Normal role: Calcium is incorporated into skeletal mineral.

Recorded consequence: Skeletal mineralization failed in assessed embryos.

Scope: Mouse developmental knockout.

Tooth dentin depends on mineral-processing enzymes as well as mineral supply.

Condition: machinery_impairment · Phospho1 deletion, with additional Alpl haploinsufficiency.

Normal role: Calcium phosphate mineral reinforces dentin.

Recorded consequence: Dentin mineralization was reduced.

Scope: Mouse incisors.

RANK is necessary for normal formation of bone-resorbing cells in this mouse model.

Condition: machinery_impairment · Rank deletion.

Normal role: Bone mineral supplies a regulated calcium reservoir.

Recorded consequence: Osteoclast formation and remodeling were impaired.

Scope: Mouse knockout/rescue.

When dietary calcium was severely restricted, osteocyte RANKL helped drive withdrawal from bone.

Condition: nutrient_deficiency · Severely calcium-deficient diet for 30 days.

Normal role: Dietary calcium supplies mineral without requiring excessive skeletal withdrawal.

Recorded consequence: RANKL-dependent bone resorption increased.

Scope: Adult mouse dietary experiment.

In these children, replacing calcium helped heal rickets.

Condition: nutrient_deficiency · Rickets in children with low dietary calcium intake.

Normal role: Calcium contributes mineral substrate to the growing skeleton.

Recorded consequence: Calcium-containing arms more often reached the healing endpoint.

Scope: Nigerian pediatric trial; not all rickets etiologies.

Low baseline intake did not guarantee a benefit on the primary pregnancy outcome.

Condition: nutrient_deficiency · Pregnancy in populations with estimated dietary calcium below 600 mg/day.

Normal role: Calcium supports maternal and fetal mineral physiology.

Recorded consequence: The primary preeclampsia endpoint was not significantly reduced; selected severe secondary outcomes differed.

Scope: 2006 multicountry WHO trial; population intake does not diagnose each participant.

A severe secondary outcome improved despite the null primary result.

Condition: nutrient_deficiency · Pregnancy in populations with estimated dietary calcium below 600 mg/day.

Normal role: Calcium supports maternal and fetal mineral physiology.

Recorded consequence: The primary preeclampsia endpoint was not significantly reduced; selected severe secondary outcomes differed.

Scope: 2006 multicountry WHO trial; population intake does not diagnose each participant.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Calcium: mechanism-first literature curation (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

ANKH-associated PPi: earlier transport interpretation versus extracellular ATP conversionEarly cellular PPi redistribution and oocyte PPi uptake supported direct-transport interpretations; later ENPP1 deletion separated ATP release from PPi appearance. Research comparison category: mechanism_and_model_difference.Read the recorded disagreement
Acute iron absorption and long-term iron status are different outcomesMeal-level absorption inhibition cannot be extrapolated into inevitable iron deficiency. Adaptation is a candidate explanation; these experiments do not establish its molecular basis.Read the recorded disagreement
Adenoma recurrence findings were not consistent across trialsEarlier and later trials differed in participants and treatment design. Overlapping confidence intervals and differing statistical significance alone do not prove contradictory biological effects. The discrepancy remains unexplained.Read the recorded disagreement
CaSR variant direction changes the calcium phenotypeReduced receptor activity and increased receptor activity cause opposite blood-calcium disturbances.Read the recorded disagreement
Calcium-overload permeability transition is not a universal apoptosis pathwayBaines 2005 reports resistance to calcium-overload/oxidative injury after Ppif loss but retained susceptibility to several other death stimuli.Read the recorded disagreement
Calcium-stabilized E-cadherin structure does not guarantee soluble self-associationA two-domain crystal displayed dimer contacts, whereas the isolated full ectodomain did not self-associate in the solution study. Research comparison category: construct_and_assay_difference.Read the recorded disagreement
Cardiovascular findings vary by trial and event ascertainmentThe calcium-only signal weakened with registry ascertainment, while WHI tested calcium plus vitamin D and a different endpoint. Neither supplies a universal risk estimate or proves coronary calcification as mechanism.Read the recorded disagreement
Dietary calcium context and combined supplements have different stone findingsThe dietary trial changed protein and salt as well as calcium and enrolled male recurrent stone formers; WHI tested calcium plus vitamin D in postmenopausal women. Luminal oxalate binding is plausible but cannot by itself reconcile all clinical differences.Read the recorded disagreement
Fracture outcomes differ across calcium-plus-vitamin-D trialsAge, baseline nutrition, setting, adherence and background supplementation differ. These are potential explanations, not demonstrated mediation or proof of a single responder threshold.Read the recorded disagreement
MICU1 pore occlusion versus allosteric potentiationGarg 2021 interprets currents as MICU-dependent potentiation without occlusion; Tsai 2023 directly observes MICU1 inhibition and identifies preparation/subunit-composition effects.Read the recorded disagreement
PTH-associated resorption versus intermittent PTH support of osteoblast survivalCalcium restriction with secondary hyperparathyroidism and daily PTH injections examine different exposure patterns and cellular outcomes.Read the recorded disagreement
Preeclampsia incidence and eclampsia are separate endpointsA null primary endpoint and a favorable severe secondary endpoint can coexist. Reporting only the secondary result would overstate the trial conclusion.Read the recorded disagreement
Preterm-birth noninferiority differed between India and TanzaniaThe same noninferiority margin was met in India but not Tanzania. This is an uncertainty/design distinction, not proof of harm in Tanzania; population explanations remain hypotheses.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

How much human bone mineral passes through each amorphous precursor pathway in vivo?The selected precursor study resolves zebrafish fin-bone maturation, not quantitative flux through all human mineralization routes.
What determines the relative ANKH-dependent ATP, citrate and possible PPi transport contributions across human tissues?Heterologous uptake and efflux assays differ in direction, cell system and ectonucleotidase expression.
What human intake threshold activates the osteocyte-RANKL skeletal response?The direct dietary mechanism study used severely calcium-restricted adult mice; it supplies no human dose-response threshold.
Does greater calcium intake enhance clotting or adhesion when extracellular calcium is already regulated?Purified-protein calcium dependence does not establish a benefit from additional oral calcium.
Which mechanisms explain different fracture, cardiovascular and adenoma trial results?Selected trials test outcomes, not all proposed mediators; no mechanistic reconciliation has been demonstrated here.
Calcium requirements, upper limits, treatment doses and medicine timing are not prescribed by this dataset.Historical study regimens are preserved as exposure data; clinical decisions and contemporary guidelines require separate evaluation.
Calcium insufficiency, reduced absorption, normal serum calcium, low ionized calcium and impaired signaling are distinct conditions.No single result diagnoses all of these states or proves a whole-organism chain reaction.
More dietary calcium does not imply a proportional increase in intracellular calcium signaling.Transport and homeostasis intervene; no linear intake-to-signaling effect was measured by the selected clinical trials.
The exact cellular target underlying acute calcium inhibition of human iron absorption remains unassigned here.The cited studies measured flux and proposed a mucosal site; they did not identify a causal named transporter.
This collection is not a systematic review of every calcium study or the latest treatment guideline.It stores selected primary experiments with explicit scope; pediatric, renal, pregnancy and other clinical applications need dedicated evidence assessment.
The fractional human contribution of TRPV6, calbindin and alternative intestinal transport routes across ages and intakes is not established by these records.Most causal deletion experiments are in mice; uptake assays and diets differ.
The full machinery sustaining residual active transport after Trpv6/calbindin double deletion is unresolved here.Residual transport demonstrates redundancy without identifying every compensating route.
Claudin-16/19 data do not justify a universal calcium-specific pore model.Heterologous cation-selectivity effects depend on background junction proteins and do not isolate calcium permeability.
No single serum-calcium measurement in this module diagnoses chronic dietary calcium insufficiency.Homeostatic compensation and calcium partitioning confound intake inference.
The magnitude of FGF23-mediated renal calcium conservation in ordinary human nutrition remains unquantified here.The causal TRPV5 trafficking evidence is predominantly from mouse and ex vivo systems.
These studies do not establish how dietary calcium insufficiency changes the amplitude or frequency of each intracellular calcium signal in humans.Most experiments change protein function, agonists, isolated-store loading or assay calcium rather than dietary intake.
The quantitative contributions of PMCA, NCX, SERCA and mitochondrial transport remain cell-type and state dependent.Purified proteins and expression systems cannot provide a universal partition of in vivo calcium flux.
MICU-dependent uptake thresholds and gating behavior across intact human tissues remain incompletely transferable from these assays.Preparation, subunit stoichiometry, calcium range and compensatory protein expression affect interpretation.
A calcium-saturated structure does not by itself quantify contraction, secretion, or kinase output in an intact organism.Binding and regulatory structures need functional and tissue context.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

Calcium

The mechanisms

Extracellular calcium activates cloned bovine CaSR expressed in Xenopus oocytes.

CaSR potentiation by NPS R-568 strengthens extracellular-calcium-mediated inhibition of PTH secretion in bovine parathyroid cells.

Inactivating CASR variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism.

The CaSR E128A variant increases receptor responsiveness and causes dominant hypocalcemia in the studied family.

PTH increases TRPV5 activity through cAMP-PKA-dependent phosphorylation at T709 in receptor/channel expression assays.

Thyroparathyroidectomy nearly abolished calcitriol production in low-calcium-fed rats; parathyroid extract restored it.

Calcitriol administration suppresses parathyroid PTH transcription in rats without a measured rise in serum calcium.

Recombinant FGF23 lowers renal CYP27B1 mRNA before the fall in serum phosphate.

Recombinant FGF23 raises renal CYP24A1 mRNA as circulating calcitriol declines.

Alpha-Klotho cooperates with FGFR1(IIIc) to confer high-affinity binding and signaling by FGF23.

FGF23 increases renal distal-tubular TRPV5 membrane abundance through FGFR/alpha-Klotho signaling involving ERK1/2, SGK1 and WNK4.

VDR-ablated mice develop hypocalcemia around postnatal day 21 with rising PTH.

A mineral/lactose rescue diet normalizes ionized calcium in VDR-ablated mice.

Trpv6 deletion reduced intestinal calcium absorption by about 60% in the Bianco mouse model.

Significant active duodenal calcium transport persists in Trpv6/calbindin-D9k double-null mice under the tested stimulation conditions.

Calcitriol induces human TRPV6 transcription through VDR/RXR-associated regulatory elements in intestinal cell models.

Claudin-2 manipulation changes calcium permeability across Caco-2 epithelial monolayers.

Claudin-12 knockdown/overexpression alters calcium permeability in Caco-2 monolayers.

Cldn2/Cldn12 double deletion lowers colonic calcium permeability; small-intestinal permeability was unchanged.

Cldn2/Cldn12 double-null mice lose more urinary calcium than Cldn2-null mice.

Trpv5-null mice have impaired distal calcium reabsorption and severe hypercalciuria despite increased vitamin D levels.

Trpv5-null mice show increased intestinal absorption of orally administered calcium tracer.

Claudin-16/19 coexpression increases paracellular cation selectivity in LLC-PK1 epithelial monolayers.

Biallelic CLDN19 variants were identified in families with renal magnesium wasting, hypercalciuria and nephrocalcinosis.

Intestinal Atp2b1 deletion prevented the active-calcium-transport increase elicited by calcitriol in control mice.

Reducing calcium intake from 2000 to 300 mg/day increased intact PTH within one week in nine healthy women.

The same diet reduction increased fractional oral 47Ca retention within one week.

In 691 patients with stage 3-5 CKD, total calcium showed only fair agreement with ionized-calcium classification.

Common albumin-adjusted calcium formulas generally classified ionized calcium no better than unadjusted total calcium in a 22,658-adult comparison.

Mice with intestinal Vdr deletion maintained serum calcium despite calcium malabsorption and impaired skeletal mineral storage.

Recombinant human CYP27B1 converts calcifediol to calcitriol by 1-alpha-hydroxylation in reconstituted enzyme systems.

Human CYP24A1 hydroxylates calcitriol to 1-alpha,24,25-trihydroxyvitamin D3 in the first C24-oxidation step.

Cloned rabbit ECaC, now termed TRPV5, confers calcium influx when expressed in Xenopus oocytes.

Rat CaT1, now termed TRPV6, mediates electrogenic calcium uptake when expressed in Xenopus oocytes.

Calcium-loaded calmodulin forms the Ca2+/CaM regulatory complex resolved with a myosin-light-chain-kinase target peptide.

Calcium/calmodulin binding folds the human calcineurin regulatory region and supports displacement of autoinhibition.

Calcineurin binds NFAT1 and supports its reversible dephosphorylated, nuclear-active state during calcium stimulation.

Calcium/calmodulin stimulates autophosphorylation of purified brain CaMKII.

Partial autophosphorylation generates CaMKII activity that persists in the absence of calcium in the purified assay.

Applied IP3 releases calcium from a nonmitochondrial intracellular store in permeabilized pancreatic acinar cells.

Human ITPR3 forms a calcium-release channel with an open pore in the IP3/ATP/Ca2+-bound structural state.

Calcium binding participates in ITPR3 gating after IP3/ATP priming, with both active and inactive calcium-bound conformations resolved.

ER-store depletion causes STIM1 to redistribute into peripheral puncta through a mechanism requiring its luminal calcium-sensing region.

STIM1 knockdown suppresses store-depletion-triggered calcium influx in HeLa cells.

The cytosolic CRAC-activation domain of STIM1 binds ORAI1 directly and activates its calcium current.

ORAI1 supplies the calcium-selective CRAC pore; transmembrane substitutions alter calcium and monovalent-ion permeability.

Homozygous ORAI1 R91W loss of function abolishes CRAC activity in patient T cells; wild-type ORAI1 restores influx.

Human SERCA2b couples its ATPase cycle to sequestration of cytosolic calcium into the ER.

Human PMCA1 is an ATP-driven plasma-membrane calcium extrusion pump characterized structurally with neuroplastin.

Neuroplastin binds the transmembrane region of human PMCA1 and supports pump ATPase activity.

Calmodulin increases apparent calcium affinity and ATPase activity of the erythrocyte calcium pump.

Human cardiac NCX1 exchanges calcium and sodium in opposing directions across the membrane.

Calcium binding to the cytosolic CBD2 regulatory domain disrupts an inactive NCX1 assembly and permits exchange.

Purified skeletal-muscle RyR1 forms an intracellular calcium-release channel with ligand-dependent open and closed states.

Calcium binds an activating RyR1 site and primes gating; ATP and caffeine increase open-state representation in the experimental preparation.

MCU supplies the inner-mitochondrial-membrane calcium-conducting pore and promotes agonist-evoked matrix calcium uptake.

MCU silencing sharply reduces mitochondrial calcium uptake while membrane potential and respiration remain intact in the tested preparations.

MICU1 limits MCU-dependent calcium uptake at low external calcium in the examined cell preparations.

MICU1 knockdown elevates basal matrix calcium through MCU-dependent uptake in the tested cells.

Calcium-responsive EF hands in MICU1 and MICU2 allow the uniporter to pass from restrained low-calcium uptake to uptake above a threshold.

Garg and colleagues interpret mitochondrial currents as MICU-dependent enhancement of uniporter opening at elevated external calcium, without pore occlusion.

Purified MICU1 suppresses MCU-complex currents in patch-clamp experiments, and disruption of its MCU-interacting K126 residue abolishes this suppression.

Calcium binds the regulatory site of cardiac troponin C; the calcium-loaded ternary structure supports altered inhibitory troponin-I interactions with actin.

Calcium binding to synaptotagmin 1 participates in triggering evoked neurotransmitter release at mouse synapses.

A synaptotagmin-1 knock-in mutation reducing calcium affinity also reduces the calcium sensitivity of evoked neurotransmitter release.

Localized sarcoplasmic-reticulum calcium release generates brief calcium sparks in rat cardiac myocytes.

Increasing sarcoplasmic-reticulum calcium content raises spontaneous release activity and permits some sparks to initiate propagating calcium waves.

Calcium-overload conditions induce cyclophilin-D-sensitive mitochondrial permeability transition and swelling in the tested mouse preparations.

Ppif-null hepatocytes and fibroblasts resist calcium-overload-induced death relative to wild type.

Mature zebrafish fin-ray bone contains crystalline carbonated apatite platelets embedded in an organized collagen matrix.

Amorphous calcium phosphate in newly forming zebrafish fin bone and increasing crystallinity with maturation support an amorphous-precursor model.

Human enamel crystallites have an apatite lattice containing calcium and phosphate, with heterogeneous magnesium, sodium, fluoride and carbonate substitutions.

Human PHOSPHO1 hydrolyzes phosphoethanolamine, releasing inorganic phosphate and ethanolamine; the enzyme requires Mg2+ in the assay.

Human PHOSPHO1 also hydrolyzes phosphocholine, producing inorganic phosphate and choline.

Active PHOSPHO1 was detected inside osteoblast-derived matrix vesicles; phosphoethanolamine hydrolase activity became accessible after vesicle sonication.

ALPL/TNAP hydrolyzes extracellular pyrophosphate to inorganic phosphate, reducing an inhibitor of matrix mineralization.

In Alpl-deficient mice and osteoblast preparations, excess pyrophosphate accompanied poor mineralization; removing Enpp1 normalized pyrophosphate and improved mineral deposition.

Combined loss of PHOSPHO1 and ALPL prevented skeletal mineralization in the reported double-null mouse embryos.