GPR68, also known as OGR1 (Ovarian Cancer G-Protein Coupled Receptor 1), is a proton-sensing G-protein coupled receptor that plays important roles in cellular pH homeostasis and stress responses. As a pH sensor in the brain, GPR68 is activated by extracellular acidosis that occurs during neuroinflammation, ischemia, and neurodegeneration, making it a potential therapeutic target for neurodegenerative diseases. [1]
GPR68 is encoded by the GPR68 gene and belongs to the proton-sensing GPCR family (including GPR4, GPR65, GPR132). Key features include:
GPR68 functions as a molecular sensor of tissue acidosis, a common feature of neuroinflammation and ischemic injury. [2]
GPR68 modulators work through acid-sensing and pro-survival signaling:
Acid-Sensing Neuroprotection: In acidic environments characteristic of neuroinflammation and ischemia, GPR68 activation triggers pro-survival signaling through Ca²⁺ release and PKC activation. [1:1]
Calcium Signaling: Gq-mediated IP3 production leads to ER Ca²⁺ release, activating calmodulin-dependent survival pathways.
ERK1/2 Activation: GPR68 signaling activates ERK1/2, promoting expression of anti-apoptotic proteins (Bcl-2, Bcl-xL).
pH Homeostasis: The receptor contributes to cellular pH regulation, important during metabolic stress.
GPR68 modulators may benefit AD through:
GPR68 is relevant for PD:
GPR68 remains an early-stage target. Approaches include:
| Approach | Development Stage | Notes |
|---|---|---|
| Small molecule agonists | Preclinical | Mimic acid-sensing |
| Positive allosteric modulators | Discovery | Enhance sensitivity |
| pH-modulating therapies | Adjunct approach | Increase tissue pH |
| Property | Value |
|---|---|
| Target | GPR68 (OGR1, GPR68) |
| Drug Class | Proton-sensing GPCR modulator |
| Endogenous Activator | Protons (H⁺) |
| Signaling | Gq-coupled |
GPR68 is an emerging target with key challenges:
Liu B, et al. GPR68: proton-sensing and neuroprotection in acidic brain environments. Cell Calcium. 2018. ↩︎ ↩︎
Muller J, et al. Targeting proton-sensing GPCRs in neurodegenerative disease. Pharmacol Rev. 2020. ↩︎
Chen H, et al. GPR68 in cerebral ischemia and neuroprotection. J Cereb Blood Flow Metab. 2021. ↩︎