Affinage

GUCY1B1

Guanylate cyclase soluble subunit beta-1 · UniProt Q02153

Length
619 aa
Mass
70.5 kDa
Annotated
2026-06-10
44 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GUCY1B1 (β1 subunit, alias GUCY1B3) encodes one of the two obligate subunits of soluble guanylyl cyclase (sGC), the nitric oxide (NO) receptor that synthesizes cGMP; co-expression of GUCY1B1 with the α1 subunit (GUCY1A3) in heterologous cells is sufficient to assemble a catalytically active, cGMP-producing heterodimer (PMID:1980215, PMID:36442224). Functional output requires both subunits in concert: in vivo, only combined loss of α1 and β1 abolishes sGC-dependent vascular and smooth-muscle responses, whereas knockdown of either alone is insufficient (PMID:33716783). Through this NO/sGC/cGMP axis, GUCY1B1 mediates a range of tissue-level processes—nitrergic gastrointestinal smooth muscle relaxation, in which it operates jointly in smooth muscle cells and interstitial cells of Cajal so that both populations are required for complete relaxation and normal gut transit (PMID:23528627); cardioprotection against ischemia-reperfusion injury via downstream PKCε/Akt signaling (PMID:30485489); and retinal neuroprotection against oxidative stress in vascular and neuronal cells (PMID:40249725). Downstream signaling proceeds through cGMP-dependent protein kinase (PKG) and its substrate VASP (PMID:24041655, PMID:35089807). GUCY1B1 transcription is positively controlled by FoxO4, which binds FoxO motifs in the GUCY1B3 promoter, and by Notch signaling acting through coactivators MAML2 and FRYL, while hypertension represses sGC by suppressing this Notch pathway (PMID:28465505, PMID:35089807); post-transcriptionally, Gucy1b1 mRNA is targeted for degradation by miR-466b-3p (PMID:41830717). In tumor and developmental settings the same axis is co-opted, contributing to glioma angiogenesis via cGMP-dependent VEGF expression (PMID:15201957) and to Notch-driven endothelial-to-mesenchymal transition during cardiac valve development (PMID:21839921).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1990 Medium

    Established that GUCY1B1 encodes a distinct ~70-kDa β subunit of the soluble guanylyl cyclase heterodimer with tissue-selective expression, defining the molecular identity of the gene.

    Evidence PCR-based cDNA cloning and tissue mRNA expression profiling

    PMID:1980215

    Open questions at the time
    • Did not demonstrate enzymatic activity of the reconstituted heterodimer
    • Subunit stoichiometry and NO-binding role not yet assigned
  2. 2004 Medium

    Linked GUCY1B1-dependent cGMP production to a pro-angiogenic program, showing the axis can drive VEGF expression and tumor vascularization in glioma.

    Evidence Antisense knockdown in human glioma cell lines with cGMP, VEGF, HUVEC angiogenesis, and xenograft readouts

    PMID:15201957

    Open questions at the time
    • Mechanism linking cGMP to VEGF transcription not resolved
    • Single-gene antisense without rescue
  3. 2011 Medium

    Placed GUCY1B1 within a Notch-driven autocrine NO/sGC loop required for endothelial-to-mesenchymal transition in valve development, extending its role beyond mature smooth muscle.

    Evidence Genetic/pharmacological Notch manipulation in vivo and in vitro with EndMT functional assays

    PMID:21839921

    Open questions at the time
    • Direct transcriptional control of GUCY1B1 promoter by Notch not demonstrated here
    • Relative contribution of β1 vs α1 not separated
  4. 2013 High

    Defined the cellular basis of nitrergic gastrointestinal relaxation, showing GUCY1B1 acts jointly in smooth muscle cells and interstitial cells of Cajal so that both are required for complete NO-induced relaxation.

    Evidence Cell-specific conditional knockout of GUCY1B3 in SMCs, ICCs, or both, with isometric force and gut transit measurements

    PMID:23528627

    Open questions at the time
    • cGMP effector steps downstream in each cell type not dissected
    • Does not address other smooth muscle beds
  5. 2013 Medium

    Connected Notch signaling to GUCY1B1 transcription and downstream PKG/VASP output, positioning Notch as a positive upstream regulator of the NO/sGC pathway.

    Evidence Notch3 activation and DAPT inhibition in ovarian epithelial/cancer cells with cGMP, PKG, and VASP phosphorylation readouts

    PMID:24041655

    Open questions at the time
    • No direct promoter occupancy by Notch effectors shown
    • Whether effect is direct or indirect unresolved
  6. 2017 Medium

    Identified the Notch coactivators MAML2 and FRYL as controllers of sGC expression and showed hypertension represses GUCY1B1 by suppressing this Notch axis, curtailing NO-dependent vasorelaxation.

    Evidence Angiotensin II hypertension model with gain/loss of Notch signaling, protein expression, and vasorelaxation assays across mouse, rat, and human data

    PMID:28465505

    Open questions at the time
    • Direct binding of MAML2/FRYL complex to the GUCY1B1 promoter not shown
    • Causality of repression in human hypertension inferred from expression
  7. 2018 Medium

    Established a cardioprotective function for GUCY1B1 against ischemia-reperfusion injury and traced it to PKCε/Akt signaling.

    Evidence Overexpression and siRNA silencing in neonatal rat ventricular myocytes plus mouse coronary ligation, with pharmacological PKC/Akt inhibitors and echocardiography

    PMID:30485489

    Open questions at the time
    • How sGC/cGMP couples to PKCε/Akt activation mechanistically not defined
    • Single lab; α1 subunit involvement not addressed
  8. 2021 Medium

    Demonstrated genetically that both subunits together are required for sGC-mediated vascular blood flow regulation, confirming obligate heterodimer function in vivo.

    Evidence CRISPR mutant and combined/individual morpholino knockdown of gucy1a1 and gucy1b1 in zebrafish with blood flow measurement and pharmacological sGC stimulation rescue

    PMID:33716783

    Open questions at the time
    • Morpholino off-target effects inherent to method
    • cGMP measurement performed in α1 mutant, not β1-specific
  9. 2022 High

    Identified FoxO4 as a direct transcriptional activator of GUCY1B1 in vascular smooth muscle, with opposing roles for FoxO1/FoxO3, establishing isoform-specific transcriptional control of the gene.

    Evidence shRNA knockdown of FoxO family members in aortic SMCs with qRT-PCR, cGMP, promoter luciferase, and ChIP

    PMID:35089807

    Open questions at the time
    • Mechanism of opposing FoxO1/FoxO3 effect not resolved
    • Interplay with Notch regulation not integrated
  10. 2023 Medium

    Confirmed by reconstitution that co-expression of α1 and β1 subunits alone is sufficient to form a catalytically active cGMP-producing enzyme.

    Evidence Lentiviral co-expression of GUCY1A3 and GUCY1B3 in HEK293 cells with sGC activity and cGMP assays

    PMID:36442224

    Open questions at the time
    • No structural or stoichiometric characterization
    • NO-responsiveness of the reconstituted enzyme not tested here
  11. 2025 Medium

    Extended GUCY1B1 function to retinal neuroprotection, localizing sGC to retinal vascular and neuronal cells and showing pharmacological sGC activation counteracts oxidative-stress damage.

    Evidence Immunohistochemistry plus in vitro/in vivo sGC activity assays and functional retinal readouts in rat IR and STZ-diabetic models

    PMID:40249725

    Open questions at the time
    • β1-specific genetic loss-of-function in retina not performed
    • Downstream cGMP effectors in neurons not identified
  12. 2025 Medium

    Revealed post-transcriptional control of Gucy1b1 by a non-coding RNA network in alveolar epithelial injury, with miR-466b-3p directly targeting its mRNA.

    Evidence Transcriptomic sequencing, pathway component manipulation, and dual-luciferase reporter assay in LPS-stimulated rat alveolar epithelial cells

    PMID:41830717

    Open questions at the time
    • sGC enzymatic/cGMP consequence of Gucy1b1 repression not measured
    • Single lab; ASIC1a/lncRNA axis not validated in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple converging transcriptional (FoxO4, Notch/MAML2/FRYL) and post-transcriptional (miR-466b-3p) regulators are integrated to set GUCY1B1 levels across tissues, and the structural basis of NO sensing by the β1 subunit, remain unresolved.
  • No unified model linking the distinct regulatory inputs
  • No structural characterization of the β1 NO-binding module in the timeline
  • Tissue-specific effector pathways downstream of cGMP only partially mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 2 GO:0016740 transferase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3
Partners
GUCY1A3
Complex memberships
soluble guanylyl cyclase (sGC) heterodimer

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 GUCY1B1 (GC-S beta 1) encodes a 70-kDa subunit of the soluble guanylyl cyclase heterodimer, preferentially expressed in lung and brain; a related beta subunit (GC-S beta 2) is preferentially expressed in kidney and liver, demonstrating heterogeneity among heterodimeric forms of guanylyl cyclase. PCR-based cDNA cloning, amino acid sequence analysis, mRNA expression profiling across tissues Biochemistry Medium 1980215
2011 Notch activation induces transcription of both sGC subunits GUCY1A3 and GUCY1B3 (the nitric oxide receptor heterodimer) during endothelial-to-mesenchymal transition in the atrioventricular canal; this Notch-dependent autocrine NO/sGC loop is necessary to drive early EndMT in valve development. Genetic and pharmacological activation/inhibition of Notch signaling in vivo and in vitro, gene expression analysis, functional assays of EndMT Developmental cell Medium 21839921
2013 GUCY1B3 (β1 subunit of NO-sensitive guanylyl cyclase) is expressed in both smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs) of the murine fundus; deletion from either SMCs or ICCs alone incompletely reduced NO-induced relaxation, but combined SMC/ICC-specific deletion completely abolished nitrergic relaxation and increased gut transit time, demonstrating that ICCs and SMCs jointly mediate enteric NO signaling. Cell-specific conditional knockout (Cre-lox) of GUCY1B3 in SMCs, ICCs, or both; isometric force studies; gut transit time measurement Gastroenterology High 23528627
2013 Notch3 activation in immortalized ovarian surface epithelial cells increases GUCY1B3 expression, NO-induced cGMP production, and PKG expression, thereby enhancing phosphorylation of VASP (a direct PKG substrate); conversely, Notch inhibition by DAPT reduces GUCY1B3 expression and NO-induced cGMP production, placing Notch as a positive upstream regulator of NO/sGC signaling. Forced Notch3 activation and DAPT-mediated Notch inhibition in IOSE and ovarian cancer cells; cGMP production assay; VASP phosphorylation western blot; sGC inhibitor ODQ cell growth assay Cellular signalling Medium 24041655
2017 Hypertension-induced (angiotensin II) repression of GUCY1B3/GUCY1A3 in the mouse aorta occurs via the Notch signaling pathway; the Notch coactivators FRYL and MAML2 are reduced by hypertension, and gain/loss-of-function experiments demonstrated that JAG/NOTCH signaling together with MAML2 and FRYL controls sGC expression. Reduced sGC was associated with curtailed NO-dependent vasorelaxation. Angiotensin II hypertension model in mice; gene expression analysis (Western blot, immunohistochemistry); transcription factor binding motif analysis; gain and loss of Notch signaling; functional vasorelaxation assays; RNA-Seq in human coronary artery Scientific reports Medium 28465505
2022 FoxO4 is a critical transcriptional activator of GUCY1B3 (sGCβ) in vascular smooth muscle cells (SMCs); FoxO4 knockdown caused ~50% decrease in GUCY1B3 mRNA and sGCβ protein, with >50% loss of cGMP production and PKG-dependent phosphorylation. FoxO4 directly binds FoxO DNA motifs in the GUCY1B3 promoter. FoxO1 or FoxO3 knockdown paradoxically increased GUCY1B3 expression. shRNA knockdown of FoxO family members in rat aortic SMCs; qRT-PCR; Western blot; cGMP production assay; promoter luciferase assay; chromatin immunoprecipitation (ChIP) in human aortic SMCs American journal of physiology. Heart and circulatory physiology High 35089807
2018 GUCY1B3 (β subunit of sGC) exerts cardioprotective effects against ischemia-reperfusion (IR) injury; GUCY1B3 was upregulated in neonatal rat ventricular myocytes after IR, overexpression reduced IR-induced cell death and apoptosis, and these effects were mediated via PKCε/Akt signaling. In a mouse coronary ligation model, GUCY1B3 silencing aggravated cardiac dysfunction and infarct size in association with inactivation of PKCε and Akt. GUCY1B3 overexpression and siRNA silencing in neonatal rat ventricular myocytes; in vitro IR model; specific PKCδ, PKCε, and Akt inhibitors; mouse coronary artery ligation model with GUCY1B3 knockdown; echocardiography, apoptosis assays Journal of cellular biochemistry Medium 30485489
2004 GUCY1B3 (β subunit of sGC) participates in mediating cGMP production upstream of VEGF expression in glioma cells; antisense knockdown of GUCY1B3 in human glioma cell lines (CCF-STTG1 and U-87MG) markedly reduced cGMP content, VEGF expression, and in vitro angiogenic activity (HUVEC growth induction), and dramatically suppressed subcutaneous tumor formation and vascular index in nude mice. Antisense RNA transfection in glioma cell lines; cGMP measurement; VEGF expression analysis; HUVEC proliferation assay; xenograft tumor formation assay with vascular index measurement Oncology reports Medium 15201957
2023 Co-expression of GUCY1A3 and GUCY1B3 subunits via lentiviral vectors in HEK293 cells resulted in formation of functional sGC enzyme with increased catalytic activity and elevated cellular cGMP levels, demonstrating that co-expression of the two subunits is sufficient for assembly of a functional heterodimeric enzyme. Lentiviral overexpression of GUCY1A3 and GUCY1B3 in HEK293 cells; sGC enzyme activity assay; cGMP quantification; cytotoxicity assay Technology and health care Medium 36442224
2025 GUCY1B1 is expressed in retinal vascular cells and neuronal elements (retinal ganglion, bipolar, and amacrine cells) in healthy human and rodent retinas; sGC function (requiring GUCY1B1) is impaired by oxidative stress in the retina, and the sGC activator runcaciguat activates sGC in multiple retinal cell types, counteracting oxidative stress-induced damage and improving neuroretinal function and morphology in rat retinal ischemia-reperfusion and streptozotocin-diabetic models. Immunohistochemistry for sGC subunit localization; in vitro and in vivo sGC activity assays; electroretinography; optokinetic tracking; retinal morphology assessment in rat IR and STZ-diabetic models Diabetes Medium 40249725
2021 In zebrafish, combined morpholino downregulation of both gucy1a1 and gucy1b1 (but not individual knockdown of either alone) increased blood flow and linear velocity, indicating that both subunits together are required for sGC-mediated regulation of vascular blood flow. An sGC stimulator (BAY41-2272) rescued impaired cGMP production in gucy1a1 mutant larvae. CRISPR-Cas9 gucy1a1 mutant zebrafish; individual and combined morpholino knockdown of gucy1a1 and gucy1b1; blood flow parameter measurement; pharmacological sGC stimulation; cGMP assay Frontiers in physiology Medium 33716783
2025 In LPS-stimulated alveolar epithelial cells (rat RLE-6TN), ASIC1a negatively regulates LncRNA00178, which in turn acts as a sponge for miR-466b-3p; miR-466b-3p targets Gucy1b1 mRNA for degradation. ASIC1a thus suppresses Gucy1b1 expression via the LncRNA00178/miR-466b-3p axis, promoting apoptosis of alveolar epithelial cells in acute lung injury. High-throughput transcriptomic sequencing of rat lung tissue; plasmid transfection to alter ASIC1a, LncRNA00178, miR-466b-3p, Gucy1b1 expression in RLE-6TN cells; dual-luciferase reporter assay; apoptosis assays International immunopharmacology Medium 41830717

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 A new form of guanylyl cyclase is preferentially expressed in rat kidney. Biochemistry 164 1980215
2011 Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Developmental cell 140 21839921
2006 Placental growth throughout the last two thirds of pregnancy in sheep: vascular development and angiogenic factor expression. Biology of reproduction 120 17050858
2008 ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity 105 18432406
2010 Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. American journal of physiology. Endocrinology and metabolism 64 20663985
2012 Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation. PloS one 50 22506031
2013 Cell-specific deletion of nitric oxide-sensitive guanylyl cyclase reveals a dual pathway for nitrergic neuromuscular transmission in the murine fundus. Gastroenterology 48 23528627
2006 Effects of estradiol-17beta on expression of mRNA for seven angiogenic factors and their receptors in the endometrium of ovariectomized (OVX) ewes. Endocrine 46 17526946
2017 Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway. Scientific reports 38 28465505
2006 Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle. Reproduction (Cambridge, England) 33 17008469
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
2006 Isolation and characterization of ovine luteal pericytes and effects of nitric oxide on pericyte expression of angiogenic factors. Endocrine 25 16943586
2013 Notch activation augments nitric oxide/soluble guanylyl cyclase signaling in immortalized ovarian surface epithelial cells and ovarian cancer cells. Cellular signalling 20 24041655
2023 Exploring the molecular mechanism of comorbidity of autism spectrum disorder and inflammatory bowel disease by combining multiple data sets. Journal of translational medicine 19 37291580
2017 Effects of diet and arginine treatment during the luteal phase on ovarian NO/PGC-1α signaling in ewes. Theriogenology 17 28532842
2016 Aging has the opposite effect on cAMP and cGMP circadian variations in rat Leydig cells. Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology 14 27915366
2021 Gene Co-Expression Analysis Identified Preserved and Survival-Related Modules in Severe Blunt Trauma, Burns, Sepsis, and Systemic Inflammatory Response Syndrome. International journal of general medicine 12 34707398
2020 Mechanism of tanshinones and phenolic acids from Danshen in the treatment of coronary heart disease based on co-expression network. BMC complementary medicine and therapies 12 32020855
2018 Differential expression of alternative transcripts of soluble guanylyl cyclase, GYCY1a3 and GUCY1b3 genes, in the malignant and benign breast tumors. Nitric oxide : biology and chemistry 12 30597209
2016 Luteal function during the estrous cycle in arginine-treated ewes fed different planes of nutrition. Reproduction (Cambridge, England) 12 27899720
2021 Analysis of 200,000 Exome-Sequenced UK Biobank Subjects Implicates Genes Involved in Increased and Decreased Risk of Hypertension. Pulse (Basel, Switzerland) 11 34722352
2018 Effects of plane of nutrition and arginine on ovarian follicles in non-pregnant sheep: Cell proliferation, and expression of endothelial nitric oxide and its receptor. Acta histochemica 10 30591314
2023 Analysis of Rare Variants in 470,000 Exome-Sequenced UK Biobank Participants Implicates Novel Genes Affecting Risk of Hypertension. Pulse (Basel, Switzerland) 8 38090255
2018 Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease. Acta physiologica (Oxford, England) 8 29754438
2021 sGC Activity and Regulation of Blood Flow in a Zebrafish Model System. Frontiers in physiology 7 33716783
2019 Soluble guanylate cyclase contribute genetic susceptibility to essential hypertension in the Han Chinese population. Annals of translational medicine 7 31930021
2017 Effects of fetal calf serum on cGMP pathway and oocyte lipid metabolism in vitro. Reproduction, fertility, and development 7 27554265
2024 Effects of late gestational nutrient restriction on uterine artery blood flow, placental size, and cotyledonary mRNA expression in primiparous beef females. Journal of animal science 5 38785319
2023 Effect of birth rank, and placentome subtype on expression of genes involved in placental nutrient transport in sheep. Theriogenology 5 37023492
2022 FoxO4 controls sGCβ transcription in vascular smooth muscle. American journal of physiology. Heart and circulatory physiology 5 35089807
2018 Mechanical pressure unloading therapy reverses thoracic aortic structural and functional changes in a hypertensive rat model. Journal of hypertension 5 30045361
2024 Extracellular vesicle-derived TP53BP1, CD34, and PBX1 from human peripheral blood serve as potential biomarkers for the assessment and prediction of vascular aging. Hereditas 4 38173016
2025 Patient-specific gene co-expression networks reveal novel subtypes and predictive biomarkers in lung adenocarcinoma. NPJ systems biology and applications 3 40346136
2025 Simvastatin inhibits proliferation and migration, promotes oxidative stress and ferroptosis in colon cancer. World journal of gastrointestinal oncology 3 40487942
2018 The β subunit of soluble guanylyl cyclase GUCY1B3 exerts cardioprotective effects against ischemic injury via the PKCε/Akt pathway. Journal of cellular biochemistry 3 30485489
2025 Integrated Transcriptomic and Metabolomic Analysis of Rat PASMCs Reveals the Underlying Mechanism for Pulmonary Arterial Hypertension. American journal of hypertension 2 39901736
2025 Neuroprotective Effect of a Novel Soluble Guanylate Cyclase Activator Runcaciguat in Diabetic and Ischemic Retinopathy. Diabetes 2 40249725
2025 Sodium valproate drives propionylation-mediated epigenetic reprogramming to enhance mesothelin CAR-T cell therapy in solid tumors. Molecular therapy : the journal of the American Society of Gene Therapy 2 41383012
2023 Co-expression of soluble guanylyl cyclase subunits and PDE5A shRNA to elevate cellular cGMP level: A potential gene therapy for myocardial cell death. Technology and health care : official journal of the European Society for Engineering and Medicine 2 36442224
2019 Association of JAG1 gene polymorphism with systemic blood pressure in patients with obstructive sleep apnea: a prospective cohort study. Croatian medical journal 1 31686456
2026 Regulon Reconstruction Uncovers Novel Deregulated Factors in Alzheimer's Disease. Molecular neurobiology 0 41729360
2026 Integrated analysis and validation of metabolism-related genes in lung transplantation-induced cold ischemia/ reperfusion injury. PeerJ 0 41769389
2026 ASIC1a promotes alveolar epithelial apoptosis and acute lung injury through repression of the LncRNA00178/miR-466b-3p/Gucy1b1 ceRNA network. International immunopharmacology 0 41830717
2025 Shared genetic loci connect cardiovascular disease with blood pressure and lipid traits in East Asian populations. Frontiers in genetics 0 40630117

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