GPR68 (OGR1, Ovarian Cancer G-Protein Coupled Receptor 1) is a proton-sensing G-protein coupled receptor that has emerged as a potential therapeutic target for Parkinson's disease. As a pH sensor in the brain, GPR68 is activated by extracellular acidosis that occurs during neuroinflammation and dopaminergic neuron degeneration in PD, triggering pro-survival signaling pathways that can be harnessed therapeutically. [1]
GPR68 is encoded by the GPR68 gene and belongs to the proton-sensing GPCR family (including GPR4, GPR65, GPR132). In PD, key features include:
GPR68 functions as a molecular sensor of tissue acidosis, a hallmark of neuroinflammation and dopaminergic degeneration in PD. [2]
GPR68 modulators exert therapeutic effects in PD through acid-sensing and pro-survival signaling:
Acid-Sensing Neuroprotection: In acidic environments characteristic of the degenerating substantia nigra, GPR68 activation triggers pro-survival signaling through Ca²⁺ release and PKC activation, directly protecting dopaminergic neurons. [3]
Calcium-Dependent Survival Pathways: Gq-mediated IP3 production leads to ER Ca²⁺ release, activating calmodulin-dependent survival pathways that promote dopaminergic neuron viability.
ERK1/2 Anti-Apoptotic Signaling: GPR68 signaling activates ERK1/2, promoting expression of anti-apoptotic proteins (Bcl-2, Bcl-xL) that protect against oxidative stress-induced cell death.
pH Homeostasis Support: The receptor contributes to cellular pH regulation, important during the metabolic stress characteristic of PD.
Modulation of Neuroinflammation: GPR68 activation on astrocytes and microglia can modulate the neuroinflammatory environment, reducing toxic signals.
GPR68 represents a compelling target for PD therapy:
| Feature | GPR68 | GPR65 |
|---|---|---|
| Signaling | Gq-coupled | Gs/Gi-coupled |
| Key Mechanism | Calcium-dependent survival | cAMP/PKA anti-inflammatory |
| PD Relevance | Direct neuroprotection | Microglial modulation |
| Development Stage | Preclinical | Preclinical |
GPR68 modulators for PD are in early preclinical development:
| Compound Type | Development Stage | Key Properties |
|---|---|---|
| GPR68 Agonists | Preclinical | Mimic acid-sensing, promote neuroprotection |
| Positive Allosteric Modulators | Discovery | Enhance proton sensitivity |
| pH-Modulating Therapies | Adjunct approach | Increase tissue pH locally |
Potential biomarkers for GPR68-targeted therapy include:
| Property | Value |
|---|---|
| Target | GPR68 (OGR1, GPR68) |
| Drug Class | Proton-sensing GPCR modulator (agonist or PAM) |
| Indication | Parkinson's Disease |
| Therapeutic Goal | Disease modification via neuroprotection |
| Endogenous Activator | Protons (H⁺) |
| Signaling | Gq-coupled |
GPR68 modulators may be combined with:
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. ↩︎
Song K, et al. GPR68 activation protects dopaminergic neurons from oxidative stress. J Neurosci Res. 2022. ↩︎