Component

cGMP-dependent protein kinase I

Kinase identified as the target of cGMP in corpus cavernosum smooth muscle.

5 recorded relationships. Experimental role, claim status and evidence remain attached to each record.

Read recorded mechanisms Open recursive mind map

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

  1. Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required.

    cGMP-dependent protein kinase I → Phosphodiesterase 5 family source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}
    experimental_model
    Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement
    exposure
    Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP
    limitations
    Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Cattle enzyme
    plain_language
    The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself.
    primary_references
    [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    tissue_or_cell_type
    Recombinant enzyme and lung extract

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 197–208

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft

    ### sil-pkg-feedback-speeds-the-enzyme Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
    Complete structured claim and evidence

  2. Corpora cavernosa from mice lacking cGMP-dependent kinase I failed to relax when the nitric oxide and cGMP signalling cascade was activated.

    cGMP-dependent protein kinase I → Corpus cavernosum smooth muscle relaxation source_derived_draftungraded
    Experimental context and source evidence
    duration
    Acute
    evidence_access
    Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    experimental_model
    cGMP-dependent kinase I null mice compared with normal mice
    exposure
    Activation of the NO/cGMP cascade
    limitations
    A whole-body knockout rather than tissue-specific deletion; the mice also had a very low ability to reproduce, while their sperm were normal and could fertilise eggs.
    organism
    cGMP-dependent kinase I null mice compared with normal mice
    plain_language
    Corpora cavernosa from mice lacking cGMP-dependent kinase I failed to relax when the nitric oxide and cGMP signalling cascade was activated.
    primary_references
    Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997
    route
    Isolated tissue
    tissue
    Corpus cavernosum smooth muscle relaxation

    Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 56–65

    Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

    ## cgmp-dependent-kinase-i-carries-the-relaxation Corpora cavernosa from mice lacking cGMP-dependent kinase I failed to relax when the nitric oxide and cGMP signalling cascade was activated. Model/species: cGMP-dependent kinase I null mice compared with normal mice Tissue/system: Corpus cavernosum smooth muscle relaxation Exposure: Activation of the NO/cGMP cascade Route: Isolated tissue Duration: Acute Limits: A whole-body knockout rather than tissue-specific deletion; the mice also had a very low ability to reproduce, while their sperm were normal and could fertilise eggs. Primary reference: Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    Complete structured claim and evidence

  3. Raising cyclic AMP with forskolin produced similar relaxation in normal and cGMP-dependent kinase I null corpus cavernosum.

    cGMP-dependent protein kinase I → Corpus cavernosum smooth muscle relaxation source_derived_draftungraded
    Experimental context and source evidence
    duration
    Acute
    evidence_access
    Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    experimental_model
    cGMP-dependent kinase I null mice compared with normal mice
    exposure
    Forskolin
    limitations
    Shows an intact parallel cAMP route in isolated tissue; the authors conclude cAMP signalling cannot compensate for the absent cGMP cascade in vivo, which is an inference from the reproductive phenotype rather than a separate measurement.
    organism
    cGMP-dependent kinase I null mice compared with normal mice
    plain_language
    Raising cyclic AMP with forskolin produced similar relaxation in normal and cGMP-dependent kinase I null corpus cavernosum.
    primary_references
    Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997
    route
    Isolated tissue
    tissue
    Corpus cavernosum smooth muscle relaxation

    Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 67–76

    Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

    ## cyclic-amp-does-not-substitute-for-the-cgmp-route Raising cyclic AMP with forskolin produced similar relaxation in normal and cGMP-dependent kinase I null corpus cavernosum. Model/species: cGMP-dependent kinase I null mice compared with normal mice Tissue/system: Corpus cavernosum smooth muscle relaxation Exposure: Forskolin Route: Isolated tissue Duration: Acute Limits: Shows an intact parallel cAMP route in isolated tissue; the authors conclude cAMP signalling cannot compensate for the absent cGMP cascade in vivo, which is an inference from the reproductive phenotype rather than a separate measurement. Primary reference: Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.
    Complete structured claim and evidence

Where it participates (unsigned role)

  1. Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.

    Phosphodiesterase 5 family → Cyclic guanosine monophosphate source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/22798047.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f", "start_char": 0, "end_char": 799, "text_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f"}
    experimental_model
    Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling
    exposure
    Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity
    limitations
    A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Animal and human
    plain_language
    In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.
    primary_references
    [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0
    tissue_or_cell_type
    Myocardium

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 600–611

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling · source_derived_draft · unverified_draft

    ### sil-preclinical-cardiac-promise Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm. organism: Animal and human tissue_or_cell_type: Myocardium experimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling limitations: A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test. exposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity evidence_span: {"source_cache": "artifacts/sildenafil-research/22798047.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f", "start_char": 0, "end_char": 799, "text_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f"} [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0
    Complete structured claim and evidence

  2. In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction.

    Membrane-bound particulate guanylate cyclase and other non-nitric-oxide sources of cyclic GMP → Cyclic guanosine monophosphate source_derived_draftungraded
    Experimental context and source evidence
    evidence_span
    {"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"}
    experimental_model
    Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte
    exposure
    Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies
    limitations
    A review written while the definitive trial was still running, and it names that trial as the test of its own thesis.
    nutrient_topic
    Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
    organism
    Animal and human
    plain_language
    The messenger has a second source that answers to natriuretic peptides rather than nitric oxide.
    primary_references
    [sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664
    tissue_or_cell_type
    Cardiac myocyte

    Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 613–624

    AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte · source_derived_draft · unverified_draft

    ### sil-two-sources-of-the-messenger In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The messenger has a second source that answers to natriuretic peptides rather than nitric oxide. organism: Animal and human tissue_or_cell_type: Cardiac myocyte experimental_model: Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte limitations: A review written while the definitive trial was still running, and it names that trial as the test of its own thesis. exposure: Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies evidence_span: {"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"} [sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664
    Complete structured claim and evidence

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

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