Targeting GPCR Signaling in Parkinson’s Disease: From Molecular Pathology to Exercise-Based Therapeutics

Parkinson’s disease (PD) is a neurodegenerative disorder driven by a combination of genetic susceptibility and environmental factors. It is characterized by the loss of dopaminergic neurons and the subsequent development of multisystem pathology involving widespread neural circuits. This results in a presentation of heterogeneous motor and non-motor symptoms, which complicates clinical management. Exercise, as a non-pharmacological intervention, has demonstrated efficacy in ameliorating both motor deficits and select non-motor symptoms in PD. However, its mechanistic underpinnings remain inadequately defined. Accumulating evidence highlights the central regulatory role of G protein-coupled receptors (GPCRs) in PD pathogenesis. These receptors are expressed on neuronal and glial membranes, and key GPCR superfamilies, including dopamine, serotonin, glutamate, γ-aminobutyric acid, cannabinoid, adenosine, and angiotensin receptors, modulate core pathological processes such as α-syn aggregation, synaptic dysfunction, neuroinflammation, and oxidative stress. However, there is a paucity of research that has yet to be conducted on the integration of how exercise influences PD through GPCR-mediated signaling pathways. This review systematically delineates the effects of exercise on PD-related pathology via modulation of GPCR expression, activity, and downstream pathways. The synthesis of current evidence will establish a comprehensive and integrated mechanism that links exercise, GPCR signaling, and PD modification. This will provide novel theoretical and translational insights for GPCR-targeted therapeutic interventions, personalized exercise regimens, and combined treatment strategies.