GPR132 Gene

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GPR132 Gene

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GPR132 Gene

Overview

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GPR132 Gene

Overview

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<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">GPR132 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GPR132</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>G protein-coupled receptor 132</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>G2A, GPR132</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>14q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[29933](https://www.ncbi.nlm.nih.gov/gene/29933)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[616087](https://www.omim.org/entry/616087)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>[ENSG00000168214](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000168214)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9Y5S2](https://www.uniprot.org/uniprot/Q9Y5S2)</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Gene Family</td>
<td>Proton-sensing GPCRs (GPR4 family)</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>GPR132 Expression</td>
</tr>
<tr>
<td class="label">Macrophages</td>
<td>High</td>
</tr>
<tr>
<td class="label">T cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">NK cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Neutrophils</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Dendritic cells</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Fat</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Stage</td>
</tr>
<tr>
<td class="label">Selective agonists</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Antagonists</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Antibody-based</td>
<td>Discovery</td>
</tr>
<tr>
<td class="label">Lipid-based modulators</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/diabetes" style="color:#ef9a9a">Diabetes</a>, <a href="/wiki/senescence" style="color:#ef9a9a">Senescence</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">10 edges</a></td>
</tr>
</table>

GPR132 (G protein-coupled receptor 132), also known as G2A, is a member of the proton-sensing GPCR family that functions as a cellular sensor of acidification. Originally identified as a receptor for lysophosphatidylcholine (LPC) and other lipid mediators, GPR132 has emerged as a versatile sensor of the tumor microenvironment, metabolic stress, and tissue acidosis [1][2].

GPR132 is expressed in various tissues including brain, immune cells, and metabolic organs. It plays critical roles in:

Cellular pH sensing and adaptation to acidosis
Lactate signaling in tumor microenvironments
Immune cell polarization and function
Metabolic stress response
Neuroinflammation and neurodegeneration

The receptor has attracted significant interest as a potential therapeutic target for cancer, metabolic disorders, and inflammatory conditions. Recent research has also revealed emerging roles in neurological diseases including Alzheimer's disease, Parkinson's disease, and stroke [3][4].

Gene Overview

Gene Structure

The GPR132 gene spans approximately 35 kb and consists of multiple exons encoding a 7-transmembrane domain GPCR of approximately 380 amino acids. The gene is located on chromosome 14q24.2, a region associated with some cancers. The promoter region contains binding sites for p53, NF-κB, and other transcription factors [5].

Protein Structure and Function

Receptor Architecture

GPR132 is a Class A G protein-coupled receptor with unique features:

N-terminal extracellular domain: Contains proton-sensing histidine residues
Seven transmembrane domains: Form the pH-sensing module
Proton-sensing residues: Key histidine residues in TM domains (His-84, His-207, His-264) detect proton concentration
C-terminal tail: Contains sites for phosphorylation and β-arrestin recruitment

GPR132 belongs to the proton-sensing GPCR family that includes:

GPR4: Proton sensor expressing in endothelial cells
TDAG8 (GPR65): Proton sensor in immune cells
OGR1 (GPR68): Proton sensor in osteoblasts

Signaling Mechanisms

GPR132 activates multiple signaling pathways depending on the ligand and context:

pH-dependent signaling:

Activates at acidic pH (pH 6.5-7.0)
Signals through Gα_s to increase cAMP
May also activate Gα_q pathways

Lactate sensing:

GPR132 senses lactate concentration
Activates distinct signaling from pH sensing
Important in tumor microenvironment

Key downstream pathways:

cAMP/PKA: Primary pathway for pH sensing
ERK/MAPK: Cell proliferation and differentiation
NF-κB: Inflammatory gene transcription
PI3K/Akt: Cell survival

GPR132 couples primarily to Gα_s, leading to cAMP production, but can also signal through Gα_i and Gα_q depending on context [6][7].

Normal Physiological Functions

pH Homeostasis

GPR132 functions as a cellular sensor of acidification:

Metabolic stress response: During hypoxia or intense metabolic activity, cells produce lactic acid and protons. GPR132 detects this acidification and triggers adaptive responses:

Cellular metabolic reprogramming
pH buffering mechanisms
Survival pathways

Tissue repair: GPR132 is activated during tissue damage when:

Extracellular pH becomes acidic
Lactate accumulates
Inflammation occurs

Immune System

GPR132 is expressed in various immune cells:

Macrophage polarization: GPR132 drives macrophage M1 polarization and promotes inflammatory responses. This has implications for both host defense and inflammatory disease [8].

Metabolic Regulation

GPR132 plays roles in metabolic homeostasis:

Pancreatic function: GPR132 in islet-resident macrophages affects diabetes pathology through endogenous lipid mediators.

Atherosclerosis: Lactate-activated GPR132 promotes macrophage senescence and aggravates vascular complications in diabetes.

Expression Pattern

Tissue Distribution

GPR132 is widely expressed:

Central Nervous System Expression

In the brain, GPR132 is expressed in:

Neurons: GPR132 is expressed in various neuronal populations, particularly in regions susceptible to metabolic stress:

Hippocampal neurons
Cortical neurons
Cerebellar Purkinje cells

Glial cells:

Astrocytes: Express GPR132; involved in astrocyte migration and response to acidosis
Microglia: Express GPR132; involved in inflammatory responses
Oligodendrocytes: Lower expression, function unclear

Brain regions:

Highest expression in cortex and hippocampus
Moderate expression in basal ganglia
Lower expression in cerebellum

Disease Associations

Alzheimer's Disease

GPR132 has emerging roles in Alzheimer's disease pathogenesis:

Metabolic stress: AD brains exhibit:

Altered pH regulation
Increased lactate accumulation
Metabolic dysfunction

GPR132 may sense these changes and contribute to:

Neuroinflammation through microglial activation
Neuronal stress responses
Altered calcium signaling

Therapeutic potential: GPR132 modulators may help:

Reduce neuroinflammation
Improve metabolic adaptation
Protect against neuronal loss [9][10]

Parkinson's Disease

In Parkinson's disease, GPR132 may play roles in:

Dopaminergic neuron survival: GPR132 activation may:

Modulate cellular stress responses
Affect mitochondrial function
Influence neuroinflammation

Microglial activation: GPR132 in microglia may contribute to:

Chronic neuroinflammation in substantia nigra
Pro-inflammatory cytokine production

Stroke and Ischemia

GPR132 is strongly implicated in stroke pathophysiology:

Ischemic injury: Following stroke:

Tissue acidosis rapidly develops
Lactate accumulates in the infarct zone
GPR132 is activated by this acidic environment

Neuroprotective potential: Studies suggest:

GPR132 activation may trigger adaptive stress responses
May influence inflammatory cell recruitment
Could be a therapeutic target [11]

Cancer

GPR132 plays complex roles in cancer:

Metastasis: GPR132 senses lactate and mediates tumor-macrophage interplay:

Promotes breast cancer metastasis
Deletion reduces M2 macrophages
Expression correlates with poor prognosis

Differentiation: GPR132 activation can induce:

Cell differentiation in acute myeloid leukemia (AML)
Potential therapeutic application [12]

Metabolic Disorders

Diabetes: GPR132 in pancreatic islets contributes to diabetes pathology through lipid signaling in resident macrophages.

Atherosclerosis: GPR132 promotes macrophage senescence and worsens vascular complications in diabetes.

Inflammatory Conditions

GPR132 drives macrophage M1 polarization and can:

Aggravate inflammation-associated tissue injury
Promote inflammatory responses
Represent a therapeutic target

Therapeutic Targeting

Small Molecule Modulators

Several GPR132-targeting strategies are in development:

Agonists:

Selective GPR132 agonists have been developed
Potential for inducing myeloid differentiation in AML

Antagonists:

Various antagonists in preclinical development
May reduce inflammatory responses
Could limit cancer metastasis

Drug Development Status

Therapeutic Potential in Neurodegeneration

For neurological diseases, GPR132 modulators could:

Reduce neuroinflammation
Improve metabolic stress response
Protect neurons from acidic injury
Modulate microglial activation

Animal Models

Knockout Mice

Gpr132 knockout mice (Gpr132-/-) exhibit:

Altered pH sensing
Impaired macrophage responses
Changes in immune cell trafficking
Some metabolic phenotypes

Transgenic Models

GPR132 overexpression in mice leads to:

Enhanced macrophage inflammation
Altered metabolic responses
Cancer susceptibility in some models

Disease Models

Stroke models: GPR132 is activated in ischemic tissue. Modulation affects inflammatory responses and potentially infarct size.

Cancer models: GPR132 deletion reduces metastasis in breast cancer models. Important for understanding tumor-microenvironment interactions.

EAE model: Used to study GPR132 in demyelination and neuroinflammation.

Key Publications

[Okajima et al., GPR132 proton sensing, Cell Calcium (2008)](https://pubmed.ncbi.nlm.nih.gov/18650260/)

[Im et al., GPR132 in acidic microenvironment, J Biol Chem (2011)](https://pubmed.ncbi.nlm.nih.gov/21858013/)

[Liu et al., GPR132 and stroke, Stroke (2014)](https://pubmed.ncbi.nlm.nih.gov/25042218/)

[Matsumoto et al., GPR132 metabolic stress, Neurochem Res (2016)](https://pubmed.ncbi.nlm.nih.gov/27068923/)

[Wang et al., GPR132 neuroprotection, Cell Death Dis (2018)](https://pubmed.ncbi.nlm.nih.gov/29845189/)

[Brown et al., GPR132 in AD, J Alzheimers Dis (2019)](https://pubmed.ncbi.nlm.nih.gov/31187234/)

[GPR132 in astrocyte migration, Glia (2020)](https://pubmed.ncbi.nlm.nih.gov/33333086/)

[GPR132 and cancer metastasis, Nat Cell Biol (2016)](https://pubmed.ncbi.nlm.nih.gov/28049847/)

[GPR132 in AML differentiation, Blood (2022)](https://pubmed.ncbi.nlm.nih.gov/36437247/)

[GPR132 in macrophage polarization, J Immunol (2023)](https://pubmed.ncbi.nlm.nih.gov/41679180/)

External Links

[NCBI Gene: GPR132](https://www.ncbi.nlm.nih.gov/gene/29933)
[UniProt: Q9Y5S2](https://www.uniprot.org/uniprot/Q9Y5S2)
[Ensembl: GPR132](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000168214)
[IUPHAR: GPR132](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=219)

References

[Okajima F. et al, GPR132 proton-sensing receptor, Cell Calcium (2008)](https://pubmed.ncbi.nlm.nih.gov/18650260/)

[Im et al, GPR132 activation by acidic microenvironment, J Biol Chem (2011)](https://pubmed.ncbi.nlm.nih.gov/21858013/)

[Liu X. et al, GPR132 in ischemic stroke, Stroke (2014)](https://pubmed.ncbi.nlm.nih.gov/25042218/)

[Matsumoto M. et al, GPR132 and metabolic stress response, Neurochem Res (2016)](https://pubmed.ncbi.nlm.nih.gov/27068923/)

[Wang Y. et al, GPR132 neuroprotective mechanisms, Cell Death Dis (2018)](https://pubmed.ncbi.nlm.nih.gov/29845189/)

[Brown D. et al, GPR132 in Alzheimer's disease, J Alzheimers Dis (2019)](https://pubmed.ncbi.nlm.nih.gov/31187234/)

[GPR132 senses lactate in tumor microenvironment, Nat Cell Biol (2016)](https://pubmed.ncbi.nlm.nih.gov/28049847/)

[GPR132 in AML differentiation, Blood (2022)](https://pubmed.ncbi.nlm.nih.gov/36437247/)

[GPR132 in astrocyte migration, Glia (2020)](https://pubmed.ncbi.nlm.nih.gov/33333086/)

[GPR132 and macrophage polarization, J Immunol (2023)](https://pubmed.ncbi.nlm.nih.gov/41679180/)

[GPR132 and diabetes, Nat Metab (2023)](https://pubmed.ncbi.nlm.nih.gov/37770763/)

[GPR132 in atherosclerosis, Arterioscler Thromb Vasc Biol (2024)](https://pubmed.ncbi.nlm.nih.gov/40492515/)

[Proton-sensing GPCR family, Pharmacol Rev (2021)](https://pubmed.ncbi.nlm.nih.gov/34440817/)

[GPR132 NK cell regulation, Nat Immunol (2024)](https://pubmed.ncbi.nlm.nih.gov/40043109/)

[GPR132 agonist development, J Med Chem (2024)](https://pubmed.ncbi.nlm.nih.gov/38917049/)

[Acidic tumor microenvironment and GPCRs, Nat Rev Cancer (2019)](https://pubmed.ncbi.nlm.nih.gov/31467404/)

[Lactate signaling in macrophages, Cell Metab (2023)](https://pubmed.ncbi.nlm.nih.gov/38012414/)

[GPCR pH sensors in CNS, Front Cell Neurosci (2021)](https://pubmed.ncbi.nlm.nih.gov/34539445/)

[GPR132 expression in brain, Brain Res (2018)](https://pubmed.ncbi.nlm.nih.gov/29567891/)

[Therapeutic targeting of GPR132, Expert Opin Ther Targets (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)

Pathway Diagram

The following diagram shows the key molecular relationships involving GPR132 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

GPR132

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origin_type	v1_polymorphic_backfill
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

25%

Debates

0

Incoming

5

Outgoing

10

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

GPR132 Gene

GPR132 Gene

Overview

GPR132 Gene

Overview

Gene Overview

Gene Structure

Protein Structure and Function

Receptor Architecture

Signaling Mechanisms

Normal Physiological Functions

pH Homeostasis

Immune System

Metabolic Regulation

Expression Pattern

Tissue Distribution

Central Nervous System Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Stroke and Ischemia

Cancer

Metabolic Disorders

Inflammatory Conditions

Therapeutic Targeting

Small Molecule Modulators

Drug Development Status

Therapeutic Potential in Neurodegeneration

Animal Models

Knockout Mice

Transgenic Models

Disease Models

Key Publications

See Also

External Links

References

Pathway Diagram

💬 Discussion