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. [@lp2018]
GPR68 Biology in Parkinson's Disease
GPR68 is encoded by the [GPR68](/genes/gpr68) gene and belongs to the proton-sensing GPCR family (including GPR4, GPR65, GPR132). In PD, key features include:
pH-Sensitive Activation: Activated by extracellular acidosis (optimal pH ~6.5), characteristic of the inflamed substantia nigra in PD
Gq-coupled Signaling: Activates phospholipase C, increasing IP3/DAG and intracellular calcium
High Brain Expression: Expressed in neurons, astrocytes, and microglia throughout the basal ganglia
Substantia Nigra Presence: Present in dopaminergic neurons of the substantia nigra pars compacta
GPR68 functions as a molecular sensor of tissue acidosis, a hallmark of neuroinflammation and dopaminergic degeneration in PD. [@mj2020]
Mechanism of Action
GPR68 modulators exert therapeutic effects in PD through acid-sensing and pro-survival signaling:
Mermaid diagram (expand to render)
Key Mechanisms in PD
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. [@sk2022]
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.
Therapeutic Rationale
Why GPR68 for PD?
GPR68 represents a compelling target for PD therapy:
Direct Neuronal Protection: Activates pro-survival pathways directly in dopaminergic neurons
Oxidative Stress Response: Particularly effective against oxidative stress-induced cell death
Non-Dopaminergic Approach: Targets neuronal survival rather than dopamine replacement
Disease-Relevant Activation: Naturally activated in PD brain, making pharmacological enhancement physiologically relevant
Comparison to Other Proton-Sensing GPCRs
Drug Development
GPR68 modulators for PD are in early preclinical development:
Challenges in GPR68 Drug Development
Brain Penetration: Developing compounds that cross the blood-brain barrier
Gq Selectivity: Achieving selectivity for Gq signaling over other proton-sensing GPCRs
Tissue-Specific Effects: Understanding how effects differ between neurons and glia
Calcium Homeostasis: Managing the narrow therapeutic window of calcium-modulating compounds
Preclinical Evidence
Animal Models
MPTP Model: GPR68 agonists protect dopaminergic neurons and improve motor function in MPTP-treated mice
Oxidative Stress Models: Reduced dopaminergic neuron loss under 6-OHDA challenge
Ischemia Models: Neuroprotection in models of cerebral ischemia, relevant to PD vascular contributions