Affinage

GUCY1A1

Guanylate cyclase soluble subunit alpha-1 · UniProt Q02108

Length
690 aa
Mass
77.5 kDa
Annotated
2026-06-10
17 papers in source corpus 10 papers cited in narrative 12 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GUCY1A1 (GUCY1A3) encodes the α1 subunit of soluble guanylate cyclase (sGC), which heterodimerizes with the β1 subunit to convert nitric oxide stimulation into cGMP production (PMID:27342234); rare coding variants from myocardial infarction patients retain β1 dimerization yet show blunted NO-stimulated cGMP output, and a Cys517Tyr loss-of-function allele as well as a catalytic-domain variant confer reduced signaling, while sGC stimulators such as BAY 41-2272 restore cGMP production (PMID:26777256, PMID:27342234, PMID:36941667). Expression of GUCY1A3 is positively controlled by the transcription factor ZEB1, which binds allele-specifically at an intronic regulatory site (rs7692387) to drive promoter activity (PMID:28487391). Functionally, sGC-derived cGMP suppresses vascular smooth muscle cell migration and potentiates NO-dependent inhibition of platelet aggregation in an allele-dependent manner (PMID:28487391). The downstream sGC–cGMP–PKG axis protects the endothelium from ferroptosis: PKG phosphorylates LDHA at Thr95, activating a moonlighting kinase function that phosphorylates GPX4 at Ser131 to block its chaperone-mediated autophagic degradation, and endothelial-specific GUCY1A1 loss enlarges no-reflow and infarct area in cardiac ischemia-reperfusion (PMID:40856046). GUCY1A3-dependent cGMP also acts upstream of VEGF/HIF-1α angiogenic signaling, supporting microvascular integrity in glioma vascularization, post-stroke recovery, and small-vessel networks (PMID:15201957, PMID:38064974, PMID:42051768).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 Medium

    Established that GUCY1A3-dependent cGMP production sits upstream of VEGF-driven angiogenesis rather than acting only as a vasorelaxant effector.

    Evidence Antisense knockdown in glioma cell lines with cGMP/VEGF readouts, HUVEC growth assay, and nude-mouse xenograft vascular index

    PMID:15201957

    Open questions at the time
    • Did not define the molecular link between cGMP and VEGF transcription
    • Antisense effects not confirmed with genetic knockout
  2. 2014 Medium

    Showed that natural GUCY1A3 coding variation tunes enzyme sensitivity, with an α1-A680T variant conferring enhanced NO responsiveness and higher cGMP output.

    Evidence cGMP production assays in reporter cells and with purified recombinant protein

    PMID:25373139

    Open questions at the time
    • Physiological consequence in highlanders inferred from association, not demonstrated mechanistically
    • Structural basis of enhanced sensitivity not resolved
  3. 2016 Medium

    Defined GUCY1A3 loss-of-function alleles in MI patients, showing variants dimerize normally with β1 but produce less cGMP, and that pharmacological sGC stimulation can rescue activity.

    Evidence Co-IP dimerization, immunoblot protein-level quantification, and cGMP radioimmunoassay of variant proteins in HEK293; plus a separate Cys517Tyr biochemical assay

    PMID:26777256 PMID:27342234

    Open questions at the time
    • In vitro HEK293 activity may not reflect native vascular cell context
    • Causal link from reduced cGMP to MI risk not demonstrated in vivo
  4. 2017 Medium

    Connected a coronary-disease risk locus to GUCY1A3 regulation and function by showing ZEB1 drives allele-specific expression and that genotype modulates sGC-dependent VSMC migration and platelet inhibition.

    Evidence Allele-specific ChIP, siRNA knockdown, reporter assay, genotype-stratified VSMC migration and ex vivo platelet aggregation assays

    PMID:28487391

    Open questions at the time
    • Single lab
    • Whether ZEB1 is the principal in vivo regulator across vascular tissues unknown
    • Mechanism linking VSMC/platelet phenotype to atherosclerotic risk not established
  5. 2023 Medium

    Demonstrated in vivo that Gucy1a3 loss impairs post-stroke vascular recovery via reduced HIF-1α/VEGFA signaling, and that GUCY1A3 is required for small-vessel but not large-artery integrity.

    Evidence Gucy1a3 knockout mice in pMCAO model with infarct, microvessel-density and pathway-marker analysis; separate KO with MR angiography, vascular casting and topology analysis

    PMID:38064974 PMID:42051768

    Open questions at the time
    • Cell-type origin of the angiogenic defect not isolated
    • Absence of large-artery stenosis leaves the moyamoya link unexplained
    • Direct mechanism coupling sGC to HIF-1α not defined
  6. 2025 High

    Resolved a downstream effector cascade by which endothelial sGC-cGMP-PKG suppresses ferroptosis through a PKG→LDHA(T95)→GPX4(S131) phosphorylation relay that stabilizes GPX4 against autophagic degradation.

    Evidence Endothelial-specific conditional KO and AAV overexpression mice, mass spectrometry phosphosite mapping, CRISPR phosphosite mutagenesis, co-IP, and cardiac ischemia-reperfusion model with vericiguat

    PMID:40856046

    Open questions at the time
    • Generality of the LDHA moonlighting kinase function beyond endothelium unknown
    • Quantitative contribution of this axis versus canonical vasorelaxation not parsed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GUCY1A3 loss-of-function alleles and the sGC-cGMP axis mechanistically cause moyamoya angiopathy and arterial hypertension in patients remains unresolved.
  • No in vivo model reproduces large-artery moyamoya stenosis
  • Catalytic-domain disease variant assessed only by structural prediction and western blot, not direct enzymatic assay

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 3 GO:0016829 lyase activity 2
Pathway
R-HSA-162582 Signal Transduction 2
Partners
GUCY1B1
Complex memberships
soluble guanylate cyclase (α1/β1 heterodimer)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 The transcription factor ZEB1 binds preferentially to the non-risk allele at rs7692387 (an intronic DNase I hypersensitivity site in GUCY1A3), and ZEB1 knockdown reduces GUCY1A3 promoter activity and endogenous GUCY1A3 expression, establishing ZEB1 as a positive transcriptional regulator of GUCY1A3 through allele-specific chromatin binding. Allele-specific chromatin immunoprecipitation, siRNA knockdown, reporter gene assay Circulation Medium 28487391
2017 Pharmacological stimulation of soluble guanylyl cyclase (sGC, whose α1 subunit is encoded by GUCY1A3) inhibits vascular smooth muscle cell migration specifically in cells homozygous for the non-risk allele of rs7692387, demonstrating that GUCY1A3-dependent sGC activity suppresses VSMC migration. Vascular smooth muscle cell migration assay with sGC stimulation, genotype-stratified Circulation Medium 28487391
2017 Ex vivo platelets from GUCY1A3 non-risk allele homozygotes show enhanced inhibition of ADP-induced platelet aggregation by the NO donor sodium nitroprusside and the PDE5 inhibitor sildenafil, demonstrating that GUCY1A3 genotype modulates sGC-dependent platelet inhibition. Ex vivo platelet aggregation assay, genotype-stratified Circulation Medium 28487391
2016 The GUCY1A3 missense variant Cys517Tyr (α1 subunit of soluble guanylate cyclase) produces a mutant protein with a significantly blunted cGMP signaling response to nitric oxide, establishing this as a loss-of-function allele that disrupts NO/cGMP signaling. Biochemical assay of cGMP production in response to NO stimulation using mutant protein Clinical genetics Medium 26777256
2016 Eight rare coding GUCY1A3 variants found in MI patients all dimerize with the β1 subunit of sGC, but five variants show significantly decreased cGMP production upon NO stimulation; one variant additionally reduces protein levels by 72%. Addition of the sGC stimulator BAY 41-2272 rescues cGMP production in all five activity-reduced variants to near wild-type levels. Co-immunoprecipitation (dimerization assay), immunoblotting (protein levels), cGMP radioimmunoassay after NO stimulation in HEK293 cells expressing GUCY1A3 variants Basic research in cardiology Medium 27342234
2014 The α1-A680T variant of GUCY1A3 (sGC α1 subunit), found in Kyrgyz highlanders without high-altitude pulmonary hypertension, confers enhanced sensitivity to nitric oxide and higher cGMP production compared to wild-type enzyme when expressed in reporter cells and in purified form in vitro. cGMP production assay in reporter cells and in vitro assay with purified recombinant protein Circulation. Cardiovascular genetics Medium 25373139
2004 Antisense knockdown of GUCY1A3 (or GUCY1B3) in glioma cell lines (CCF-STTG1, U-87MG) markedly reduced intracellular cGMP levels, decreased VEGF expression, inhibited HUVEC growth in vitro, and suppressed subcutaneous tumor formation and vascular index in nude mice, placing GUCY1A3-dependent cGMP production upstream of VEGF-mediated angiogenesis in glioma. Antisense RNA transfection, cGMP measurement, VEGF expression analysis, in vitro angiogenesis assay (HUVEC growth), in vivo xenograft model Oncology reports Medium 15201957
2025 In cardiac ischemia-reperfusion injury, the sGC-cGMP-PKG pathway (with GUCY1A1 as the α1 subunit of sGC) suppresses endothelial ferroptosis: PKG phosphorylates LDHA at threonine 95, activating LDHA's moonlighting kinase function to phosphorylate GPX4 at serine 131, thereby reducing chaperone-mediated autophagy-dependent degradation of GPX4. EC-specific GUCY1A1 knockout increased the no-reflow area and infarct size, while GUCY1A1 overexpression or the activator vericiguat alleviated microvascular dysfunction. Endothelial cell-specific conditional knockout and AAV-mediated overexpression mice; mass spectrometry identification of phosphorylation sites; CRISPR-Cas9 mutagenesis of phosphorylation sites; co-immunoprecipitation; cardiac ischemia-reperfusion model Circulation research High 40856046
2023 Loss of Gucy1a3 in mice following permanent middle cerebral artery occlusion increased infarct volume, aggravated neurological deficits, reduced microvessel density, and decreased VEGFA and HIF-1α protein expression, placing GUCY1A3 upstream of the HIF-1α/VEGFA angiogenic signaling pathway in post-stroke recovery. Gucy1a3 knockout mice, pMCAO model, TTC staining, CD31 immunohistochemistry, western blotting Journal of stroke and cerebrovascular diseases Medium 38064974
2026 In Gucy1a3 knockout mice, loss of the α1 subunit of sGC did not produce large-artery stenosis typical of moyamoya disease under basal conditions, but caused significant rarefaction of leptomeningeal vascular networks (reduced branching and density) and reduced cortical microvessel density and diameter, indicating that GUCY1A3 is required for small-vessel but not large-vessel integrity in early adult mice. 7.0T MR angiography, cerebral vascular casting, H&E/EVG staining, α-SMA immunohistochemistry, CD31 immunohistochemistry, vascular skeletonization/topology analysis in Gucy1a3-/- mice Frontiers in neurology Medium 42051768
2026 Gucy1a3 siRNA knockdown in chondrocytes phenocopied the anti-inflammatory effect of DAPT (Notch inhibitor) by suppressing iNOS and MMP13, and DAPT suppressed Gucy1a3 expression, identifying a reciprocal positive feedback loop between NO-Gucy1a3 signaling and Notch activation in chondrocytes. siRNA knockdown of Gucy1a3 in chondrocytes, Notch inhibitor DAPT treatment, gene expression analysis, rat medial meniscus resection model Drug design, development and therapy Low 42157792
2023 A homozygous GUCY1A3 missense variant (c.1778G>A) located in the catalytic domain of sGC is predicted to disrupt the 3D structure of the domain and cause loss of enzymatic function, associated with moyamoya angiopathy and early-onset arterial hypertension in a consanguineous proband. Exome sequencing, western blot (protein expression in endothelial progenitor cells), 3D protein structure analysis Human genomics Low 36941667

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus. Circulation 82 28487391
2021 RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability. Frontiers in neurology 70 34381413
2016 Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clinical genetics 65 26777256
2004 Inhibition of angiogenesis in human glioma cell lines by antisense RNA from the soluble guanylate cyclase genes, GUCY1A3 and GUCY1B3. Oncology reports 32 15201957
2019 Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin. European heart journal 31 31228190
2014 α1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circulation. Cardiovascular genetics 23 25373139
2019 Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention. Cardiovascular research 20 30768153
2016 Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants. Basic research in cardiology 20 27342234
2025 GUCY1A1-LDHA Axis Suppresses Ferroptosis in Cardiac Ischemia-Reperfusion Injury. Circulation research 9 40856046
2023 Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy. Human genomics 9 36941667
2022 SELL and GUCY1A1 Gene Polymorphisms in Patients with Unstable Angina. Biomedicines 8 36289756
2019 Associations between GUCY1A3 genetic polymorphisms and large artery atherosclerotic stroke risk in Chinese Han population: a case-control study. Lipids in health and disease 5 31883534
2023 Loss of Gucy1a3 causes poor post-stroke recovery by reducing angiogenesis via the HIF-1α/VEGFA signaling pathway in mice. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 2 38064974
2026 Cerebrovascular phenotype analysis in Gucy1a3 loss-of-function mice: insights into moyamoya disease susceptibility. Frontiers in neurology 0 42051768
2026 DAPT Mitigates Osteoarthritic Cartilage Degeneration and Enhances Articular Repair Through Targeted Modulation of the Gucy1a3 and Notch Signaling Axis. Drug design, development and therapy 0 42157792
2024 Polymorphisms of the HRG, FETUB, and GUCY1A1 genes and their association with litter size in sheep. Archives animal breeding 0 42088546
2022 [Polymorphism rs7692387 of GUCY1A1 as a genetic marker for peripheral artery disease in cigarette smokers]. Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery 0 41761525

Missed literature

Know a paper Affinage missed for GUCY1A1? Flag it for the maintainers and the community.

No submissions yet.