Research Progress of G Protein-coupled Receptor 52 on Central Nervous System Diseases

The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is locatedprincipally in the striatum alongside D2 receptor and in the pre-frontal cortex alongside D1 receptor.Its stimulation leads to potentiation of intracellular cAMP levels, producing effects oncAMP levels similar to those of a Gi-coupled D2 receptor antagonist in the striatum and a GscoupledD1 receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52activation could result in antipsychotic effects akin to D2 antagonism and pro-cognitive effectsresembling D1 agonism. As a result, GPR52 has emerged as a promising therapeutic target forcentral nervous system (CNS) disorders, including schizophrenia and substance use disorder.Additionally, knocking out (KO) GPR52 not only significantly reduces mutant huntingtin protein(mHTT) levels in the striatum but also rescues Huntington's disease-associated behavioralphenotypes in a knock-in Huntington's disease mouse model, which provides evidence thatGRP52 may also serve as a potential target for Huntington's disease. This review summarizesthe current state of small-molecule ligand/drug discovery for GPR52, focusing on the latestfindings about the role of GPR52 in schizophrenia and Huntington's disease.