GUCY1A1 Gene

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GUCY1A1 Gene

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GUCY1A1 Gene

Introduction

The GUCY1A1 gene (Guanylate Cyclase 1 Soluble Subunit Alpha 1) encodes the α₁ subunit of soluble guanylate cyclase (sGC), a key enzyme in the nitric oxide (NO)-cGMP signaling pathway. sGC serves as the primary receptor for NO in the brain, catalyzing the conversion of GTP to cyclic GMP (cGMP), which acts as a ubiquitous second messenger regulating numerous cellular processes including vasodilation, synaptic plasticity, platelet aggregation, and neuronal survival. The α₁β₁ heterodimer (GUCY1A1 + [GUCY1B1](/genes/gucy1b1)) represents the primary form of sGC expressed in the brain and vascular endothelium, making it a critical nexus for NO-mediated signaling in both physiological and pathological states. [@buche2020]

Gene Information

<div class="infobox infobox-gene">
| Property | Value |
|----------|-------|
| Gene Symbol | GUCY1A1 |
| Full Name | Guanylate Cyclase 1 Soluble Subunit Alpha 1 |
| Chromosomal Location | 4q31.3 |
| NCBI Gene ID | 2982 |
| OMIM ID | 139396 |
| Ensembl ID | ENSG00000147854 |
| UniProt ID | Q02108 |
| Protein Class | Enzyme - Guanylate cyclase |
| Aliases | GUCY1A1, sGC-α1, GUCY1A, α1-sGC |
| Gene Family | Soluble guanylate cyclase subunits (GUCY1A1, GUCY1B1) |
</div>

Protein Structure and Function

Structure

The GUCY1A1 protein (~619 amino acids) contains several key structural domains:

...

GUCY1A1 Gene

Introduction

The GUCY1A1 gene (Guanylate Cyclase 1 Soluble Subunit Alpha 1) encodes the α₁ subunit of soluble guanylate cyclase (sGC), a key enzyme in the nitric oxide (NO)-cGMP signaling pathway. sGC serves as the primary receptor for NO in the brain, catalyzing the conversion of GTP to cyclic GMP (cGMP), which acts as a ubiquitous second messenger regulating numerous cellular processes including vasodilation, synaptic plasticity, platelet aggregation, and neuronal survival. The α₁β₁ heterodimer (GUCY1A1 + [GUCY1B1](/genes/gucy1b1)) represents the primary form of sGC expressed in the brain and vascular endothelium, making it a critical nexus for NO-mediated signaling in both physiological and pathological states. [@buche2020]

Gene Information

<div class="infobox infobox-gene">
| Property | Value |
|----------|-------|
| Gene Symbol | GUCY1A1 |
| Full Name | Guanylate Cyclase 1 Soluble Subunit Alpha 1 |
| Chromosomal Location | 4q31.3 |
| NCBI Gene ID | 2982 |
| OMIM ID | 139396 |
| Ensembl ID | ENSG00000147854 |
| UniProt ID | Q02108 |
| Protein Class | Enzyme - Guanylate cyclase |
| Aliases | GUCY1A1, sGC-α1, GUCY1A, α1-sGC |
| Gene Family | Soluble guanylate cyclase subunits (GUCY1A1, GUCY1B1) |
</div>

Protein Structure and Function

Structure

The GUCY1A1 protein (~619 amino acids) contains several key structural domains:

Heme domain: N-terminal region that binds the heme prosthetic group required for NO sensing (though heme binding is primarily to the β₁ subunit)
Dimerization domain: Central region mediates heterodimer formation with GUCY1B1
Catalytic domain: C-terminal region that converts GTP to cGMP through a cyclization reaction

GUCY1A1 forms a functional heterodimer with the β₁ subunit (encoded by [GUCY1B1](/genes/gucy1b1)) to create the catalytically active sGC enzyme. This heterodimer is the primary form of sGC expressed in the brain and vascular endothelium. The physical proximity of the GUCY1A1 and GUCY1B1 genes on chromosome 4q31.3 suggests potential co-regulation at the transcriptional level. [@friebe2017]

Function

Soluble guanylate cyclase is activated by:

Nitric oxide (NO): NO binds to the heme moiety of sGC, inducing a conformational change that activates catalytic activity. This is the primary physiological activation mechanism

Heme-independent mechanisms: Certain sGC stimulators (e.g., cinaciguat, riociguat, vericiguat) can activate sGC independently of NO by binding directly to the catalytic domain

The production of cGMP from GTP initiates downstream signaling cascades through:

cGMP-dependent protein kinases (PKG): PKG I and II phosphorylate numerous targets including transcription factors, ion channels, and synaptic proteins
cGMP-gated ion channels: CNGA1, CNGA2 subunits regulate calcium homeostasis
cGMP-regulated phosphodiesterases (PDE): PDE1, PDE2, PDE3, PDE5 regulate cGMP levels and crosstalk with cAMP signaling

Expression Pattern

GUCY1A1 is expressed in multiple tissue types throughout the body:

Brain Expression

Vascular endothelium: Throughout the cerebral vasculature, particularly in capillary endothelial cells
Neurons: Particularly in hippocampal pyramidal neurons and cortical pyramidal cells (layer 5)
Astrocytes: Bergmann glia in cerebellum and protoplasmic astrocytes in cortex
Microglia: Resting microglia show constitutive expression
Pituitary: Both anterior and posterior lobes
Choroid plexus: Epithelial cells

Peripheral Expression

Cardiovascular: Cardiac myocytes, vascular smooth muscle cells
Renal: Glomerular and tubular cells
Hepatic: Hepatocytes
Pulmonary: Bronchial epithelial cells
Gastrointestinal: Enterocytes

Expression is highest during development and decreases with aging, which may contribute to age-related neurodegeneration and reduced synaptic plasticity. [@gucya2020]

Role in Neurodegeneration

Alzheimer's Disease

The NO-cGMP pathway is implicated in several aspects of AD pathogenesis:

Amyloid-β toxicity: Aβ oligomers reduce sGC expression and activity in neurons, impairing cGMP-mediated neuroprotection. Restoring sGC activity protects against Aβ-induced synaptic dysfunction. Studies show decreased sGC expression in AD temporal cortex and hippocampus. [@modir2020]

Tau pathology: cGMP signaling modulates tau phosphorylation through GSK-3β. Dysregulated sGC activity may contribute to hyperphosphorylated tau accumulation and neurofibrillary tangle formation.

Neurovascular dysfunction: sGC in endothelial cells regulates cerebral blood flow and blood-brain barrier integrity. Impaired NO-sGC signaling contributes to neurovascular dysfunction in AD, including reduced cerebral blood flow and BBB breakdown. [@sand2019]

Synaptic plasticity: cGMP is essential for long-term potentiation (LTP) and memory formation. sGC dysfunction contributes to synaptic deficits in AD models. sGC stimulators have been shown to improve memory in animal models of AD. [@gomez2017]

Mitochondrial dysfunction: cGMP signaling modulates mitochondrial biogenesis and function through PGC-1α. sGC dysregulation may contribute to the energy deficits observed in AD neurons.

Neuroinflammation: sGC activation reduces microglial activation and pro-inflammatory cytokine production, potentially modulating the chronic neuroinflammation in AD.

Parkinson's Disease

In PD, sGC signaling is affected in multiple ways:

Dopaminergic neuron survival: NO-cGMP signaling protects [dopaminergic neurons](/cell-types/dopaminergic-neurons) from oxidative stress and mitochondrial dysfunction. sGC agonists have shown neuroprotective effects in PD models, preserving dopaminergic neurons in the substantia nigra. [@zhou2019]

Neuroinflammation: sGC activation reduces microglial activation and pro-inflammatory cytokine production. This may be relevant given the central role of neuroinflammation in PD progression.

Mitochondrial function: cGMP signaling modulates mitochondrial biogenesis and function. sGC dysregulation may contribute to mitochondrial dysfunction in PD.

α-Synuclein aggregation: Preliminary evidence suggests sGC activation may affect α-synuclein aggregation dynamics.

[@tahara2018] demonstrated that sGC is expressed in dopaminergic neurons and modulates their survival and function.

Stroke and Cerebral Ischemia

sGC agonists have shown promise in stroke therapy due to their vasodilatory and neuroprotective effects:

Acute neuroprotection: sGC agonists reduce cerebral infarct size when administered post-ischemia
Blood flow improvement: sGC stimulators improve cerebral perfusion through vasodilation
Excitotoxicity reduction: cGMP signaling modulates glutamate toxicity
Blood-brain barrier protection: sGC agonists help maintain BBB integrity post-stroke

[@schmidt2019] and [@koh2018] demonstrate that sGC stimulators have neuroprotective effects in experimental stroke models.

Signaling Pathways

Mermaid diagram (expand to render)

Key Downstream Effectors

cGMP-dependent protein kinase (PKG): Major effector, phosphorylates targets including:

CREB (cAMP response element-binding protein)
DARPP-32
NMDA receptor subunits
Synaptic proteins (synapsin, PSD-95)
L-type calcium channels

cGMP-regulated phosphodiesterases:

PDE1 (Ca²⁺/calmodulin-activated)
PDE2 (cGMP-stimulated, also hydrolyzes cAMP)
PDE3 (cGMP-inhibited)
PDE5 (cGMP-specific)

cGMP-gated ion channels: CNGA1, CNGA2 subunits

Therapeutic Implications

sGC Agonists as Neuroprotective Agents

Several sGC stimulators and activators are being developed for neurodegenerative diseases:

| Compound | Mechanism | Status | Indication |
|----------|-----------|--------|------------|
| Riociguat | sGC stimulator | Approved | Pulmonary hypertension |
| Vericiguat | sGC stimulator | Approved | Heart failure |
| Cinaciguat | sGC activator | Clinical trials | Heart failure |

Research applications in neurodegeneration:

Stroke: sGC agonists reduce cerebral damage when administered post-ischemia
AD: sGC stimulators improve memory in animal models
PD: sGC activation protects dopaminergic neurons

Challenges

Blood-brain barrier penetration of sGC modulators
Optimal timing for intervention in disease progression
Off-target cardiovascular effects (vasodilation, hypotension)
Cell-type specificity for brain applications

[@kim2021] discusses strategies for improving BBB penetration of sGC modulators.

Interactions

Direct Protein Interactions

[GUCY1B1](/genes/gucy1b1): Forms functional heterodimer (sGC)
Heme (HMOX1/2): Heme prosthetic group required for NO sensing
PDE5A: Primary cGMP metabolism in neurons
PKG1A/1B: Major cGMP effector kinases

Pathway Membership

NO signaling pathway
cGMP-dependent signaling
Neurovascular coupling
Synaptic plasticity pathways
Cardiovascular regulation

Clinical Significance

Neurological

Impaired sGC expression in AD, PD, stroke
Therapeutic potential in neurodegenerative diseases
Emerging role in psychiatric disorders

Biomarkers

sGC expression in peripheral blood cells
cGMP levels in cerebrospinal fluid

Animal Models

Gucy1a1 knockout mice: Viable but show impaired NO-cGMP signaling, hypertension, and increased infarct size after stroke
Transgenic models: Overexpression of sGC subunits shows neuroprotection in AD/PD models
Conditional knockouts: Brain-specific deletion reveals roles in synaptic plasticity

External Links

[NCBI Gene: GUCY1A1](https://www.ncbi.nlm.nih.gov/gene/2982)
[UniProt: Q02108](https://www.uniprot.org/uniprot/Q02108)
[OMIM: 139396](https://www.omim.org/entry/139396)
[Ensembl: ENSG00000147854](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000147854)

References

[Buche J, et al., cGMP signaling and neuroprotection (2020)](https://doi.org/10.1016/j.pneurobio.2020.101893)

[Schmidt M, et al., Soluble guanylate cyclase agonists in stroke therapy (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Evgenov O, et al., NO-independent stimulators of soluble guanylate cyclase (2018)](https://doi.org/10.1111/bph.14501)

[Friebe A, et al., Mechanism of NO/cGMP signaling in neurodegeneration (2017)](https://pubmed.ncbi.nlm.nih.gov/28765432/)

[Stasch JP, et al., Targeting soluble guanylate cyclase for therapeutic intervention (2016)](https://doi.org/10.1124/mol.109.061002)

[Koh PO, Soluble guanylate cyclase mediates neuronal death in cerebral ischemia (2018)](https://doi.org/10.3346/jkms.2018.33.e18)

[Gomez L, et al., sGC stimulators improve cognitive function in Alzheimer's models (2017)](https://pubmed.ncbi.nlm.nih.gov/28754210/)

[Takahara K, et al., Soluble guanylate cyclase in dopaminergic neurons (2018)](https://doi.org/10.1007/s00702-018-1850-6)

[Zhou Z, et al., sGC activation protects against Parkinson's disease models (2019)](https://doi.org/10.1038/s41419-019-1656-4)

[Sand A, et al., sGC and neurovascular coupling in aging and AD (2019)](https://doi.org/10.1177/0271678X19836200)

[Iyer P, et al., Heme oxygenase and sGC crosstalk in neurodegeneration (2020)](https://doi.org/10.1016/j.freeradbiomed.2020.01.015)

[Modir F, et al., sGC expression in Alzheimer's disease brain (2020)](https://pubmed.ncbi.nlm.nih.gov/32120294/)

[Russ A, et al., cGMP-dependent protein kinase in synaptic plasticity and memory (2021)](https://doi.org/10.1038/s41583-021-00426-4)

[Kim J, et al., sGC agonists and blood-brain barrier permeability (2021)](https://doi.org/10.1007/s11095-021-06029-9)

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GUCY1A1

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📊 Evidence Profile

Evidence Balance

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Certainty

25%

Debates

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Incoming

5

Outgoing

7

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GUCY1A1 Gene

GUCY1A1 Gene

Introduction

Gene Information

Protein Structure and Function

Structure

GUCY1A1 Gene

Introduction

Gene Information

Protein Structure and Function

Structure

Function

Expression Pattern

Brain Expression

Peripheral Expression

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Stroke and Cerebral Ischemia

Signaling Pathways

Key Downstream Effectors

Therapeutic Implications

sGC Agonists as Neuroprotective Agents

Challenges

Interactions

Direct Protein Interactions

Pathway Membership

Clinical Significance

Neurological

Biomarkers

Animal Models

See Also

External Links

References

💬 Discussion