G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson’s disease

Abstract

Parkinson’s Disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BGTC in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.