{"id":"618f99d4-931e-5e78-acdb-ea892901e09a","stable_key":"5102beb6-9f61-500e-af10-9ac63649e0b7:renal-chloride-inhibits-wnk4","predicate":"inhibits","statement":"Increasing chloride inhibited recombinant WNK4 phosphorylation of SPAK more strongly than WNK1/3 in matched assays.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"56a01b2e-002c-57c1-a412-465f5e0fe011","mechanism_event_label":"Chloride restrains WNK4, a kinase upstream of sodium-chloride transport.","subject":{"id":"6f35aa38-f875-5759-b749-97a2f6480ff3","slug":"chloride-ion","display_name":"Chloride ion","entity_type_key":"ion"},"object":{"id":"60a8da52-44b6-5714-ae92-2776e6ed5aeb","slug":"wnk4","display_name":"WNK lysine deficient protein kinase 4","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"56a01b2e-002c-57c1-a412-465f5e0fe011","stable_key":"5102beb6-9f61-500e-af10-9ac63649e0b7:renal-chloride-inhibits-wnk4-event","event_type":"biochemical_relationship","label":"Chloride restrains WNK4, a kinase upstream of sodium-chloride transport.","description":"Increasing chloride inhibited recombinant WNK4 phosphorylation of SPAK more strongly than WNK1/3 in matched assays.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"6f35aa38-f875-5759-b749-97a2f6480ff3","slug":"chloride-ion","display_name":"Chloride ion","entity_type_key":"ion"},"role":"causal-subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"60a8da52-44b6-5714-ae92-2776e6ed5aeb","slug":"wnk4","display_name":"WNK lysine deficient protein kinase 4","entity_type_key":"protein"},"role":"measured-target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"6ac31e68-8970-5167-aca8-4ce8d90a66cc","slug":"stk39","display_name":"STE20/SPS1-related proline/alanine-rich kinase","entity_type_key":"protein"},"role":"substrate","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"63291643-1df9-5547-952a-9082838a350e","slug":"slc12a3","display_name":"Thiazide-sensitive sodium-chloride cotransporter","entity_type_key":"protein"},"role":"downstream-context","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"cross_nutrient","value_text":"Chloride concentration gates a kinase linking K sensing to Na transport.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_location","value_text":"Figure 3; equimolar chloride/gluconate kinase assay.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Purified kinase domains; SPAK substrate","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Does not directly measure native DCT chloride or WNK4 autophosphorylation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Potassium research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"potassium","display_name":"Potassium","entity_type_key":"nutrient_element"}},{"dimension":"organism","value_text":"Recombinant proteins","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Chloride restrains WNK4, a kinase upstream of sodium-chloride transport.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[terker-2016-wnk4-chloride] Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC4814375/ DOI: 10.1038/ki.2015.289","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cell-free assay","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"81f6d4c8-393f-5ae6-bee3-e3ca59275a59","evidence_kind":"source_excerpt","locator":"Lines 138-149","start_line":138,"end_line":149,"excerpt":"### renal-chloride-inhibits-wnk4\nIncreasing chloride inhibited recombinant WNK4 phosphorylation of SPAK more strongly than WNK1/3 in matched assays.\nCondition category: normal\nnutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Chloride restrains WNK4, a kinase upstream of sodium-chloride transport.\norganism: Recombinant proteins\ntissue_or_cell_type: Cell-free assay\nexperimental_model: Purified kinase domains; SPAK substrate\nlimitations: Does not directly measure native DCT chloride or WNK4 autophosphorylation.\ncross_nutrient: Chloride concentration gates a kinase linking K sensing to Na transport.\nevidence_location: Figure 3; equimolar chloride/gluconate kinase assay.\n[terker-2016-wnk4-chloride] Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC4814375/ DOI: 10.1038/ki.2015.289","model_system":"Purified kinase domains; SPAK substrate","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [terker-2016-wnk4-chloride] Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC4814375/ DOI: 10.1038/ki.2015.289","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"241226ee-6b7d-5cc7-9781-e6beb8ee1982","stable_key":"import-5102beb6-9f61-500e-af10-9ac63649e0b7","title":"Potassium: cross-nutrient mechanisms and deficiency (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"a8f89f8d84b48c0f93048dfc45f7f57a67dd9a7249968a096a14aeb03d8b7a52","revision_id":"de4ec6f4-58a1-537b-8169-97b783898df1","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}