GPR132 Gene
Overview
Mermaid diagram (expand to render)
<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].
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]
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/)See Also
- [GPR4](/genes/gpr4) - Related proton-sensing receptor
- [TDAG8 (GPR65)](/genes/gpr65) - Related proton-sensing receptor
- [Proton-sensing GPCRs](/mechanisms/proton-sensing-gpcr-pathway)
- [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Stroke](/diseases/stroke)
- [Lactate signaling](/mechanisms/lactate-metabolism-pathway)
- [Microglia](/cell-types/microglia-neuroinflammation)
- [Macrophages](/cell-types/macrophages)
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)