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 located principally 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 on cAMP levels similar to those of a Gi-coupled D2 receptor antagonist in the striatum and a Gscoupled D1 receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52 activation could result in antipsychotic effects akin to D2 antagonism and pro-cognitive effects resembling D1 agonism. As a result, GPR52 has emerged as a promising therapeutic target for central 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 behavioral phenotypes in a knock-in Huntington's disease mouse model, which provides evidence that GRP52 may also serve as a potential target for Huntington's disease. This review summarizes the current state of small-molecule ligand/drug discovery for GPR52, focusing on the latest findings about the role of GPR52 in schizophrenia and Huntington's disease.