GPR68, a proton-sensing GPCR, as a therapeutic target in depression: structural, signalling, and mechanistic...

Brain acid signalling refers to the process by which brain tissue utilizes protons (H⁺) as signalling molecules to sense changes in the extracellular microenvironmental pH via specific receptors such as proton-sensing GPCRs. This signalling initiates downstream pathways that regulate neural activity and maintain brain homeostasis. As a prototypical proton-sensing GPCR, GPR68 plays a pivotal role in maintaining physiological homeostasis, regulating tissue functions, and contributing to pathological processes, owing to its high sensitivity to extracellular pH changes. GPR68 is expressed in neurons distributed across multiple brain regions, including the hippocampus, cortex, striatum, and cerebellum. Emerging evidence indicates that GPR68 deficiency impairs hippocampal long-term potentiation (LTP) and passive avoidance fear memory, whereas GPR68 overexpression reduces infarct size following transient middle cerebral artery occlusion (tMCAO) in murine models. These findings emphasize the functional significance of GPR68-mediated synaptic plasticity and neuronal injury. Nevertheless, the exact mechanism underlying its role in the pathogenesis of depression remains unclear. In this review, we comprehensively summarize current knowledge regarding GPR68, including its molecular structure, expression profile, signalling pathways, and regulatory functions in depression. Collectively, these findings provide compelling evidence that GPR68 represents a promising novel therapeutic target for antidepressant development. However, challenges remain in the clinical translation of GPR68-targeted therapies, necessitating large-scale studies to validate their efficacy and safety.