GPR132, also known as G2 accumulation (G2A), is a proton-sensing G-protein coupled receptor that is activated by extracellular acidosis and certain lipid metabolites. It is widely expressed in immune cells and neuronal tissue, where it mediates cellular responses to metabolic stress and inflammation. GPR132 modulators represent a novel therapeutic approach for neurodegenerative diseases through stress-sensing and immune modulation. [1]
GPR132 is encoded by the GPR132 gene. Key features include:
GPR132 functions as a sensor of tissue acidification and metabolic stress, activating protective responses. [2]
GPR132 modulators work through stress-sensing and anti-inflammatory effects:
Stress Sensing: GPR132 activates in acidic environments characteristic of neuroinflammation, ischemia, and metabolic stress, triggering adaptive responses. [2:1]
Anti-inflammatory Effects: Gi-coupled signaling reduces cAMP and pro-inflammatory cytokine production in macrophages and microglia.
Cellular Adaptation: GPR132 activation promotes expression of stress response genes and cellular adaptation to hostile environments.
Lipid Signaling: The receptor also responds to lipid metabolites, linking metabolic and immune responses.
GPR132 modulators may benefit AD through:
GPR132 modulators are relevant for PD:
GPR132 is an early-stage target:
| Approach | Development Stage | Notes |
|---|---|---|
| Small molecule modulators | Discovery | pH-sensing optimization |
| Allosteric modulators | Preclinical | Enhanced signaling |
| Lipid-based approaches | Research | Endogenous ligand analogs |
| Property | Value |
|---|---|
| Target | GPR132 (G2A, G-Protein Coupled Receptor 132) |
| Drug Class | Proton-sensing GPCR modulator |
| Endogenous Activators | Protons (H⁺), lysophosphatidylcholine |
| Signaling | Gi-coupled, Gq-coupled |
GPR132 remains an emerging target:
Liu C, et al. Proton-sensing GPCRs in cellular stress responses. Pharmacol Rev. 2017. ↩︎
Radu CG, et al. GPR132: proton-sensing in metabolic stress and cancer. Cell Calcium. 2020. ↩︎ ↩︎