GPR52

GPR52 is an orphan G-protein-coupled receptor that is selectively expressed in the striatum and cortex with the highest level of expression in the nucleus accumbens (NAc). The selective expression of GPR52 in the NAc and other striatal regions suggests an important function for this receptor in primary striatal neurons and broader corticostriatal circuitry. Moreover, GPR52 is colocalized exclusively with dopamine D2 receptors in medium spiny neurons (MSNs) in the striatum and has lesser expression in neurons of the medial prefrontal cortex. Notably in transgenic mice, the overexpression of GPR52 significantly decreased methamphetamine-induced locomotion, while GPR52 knockout mice showed an anxiolytic-like phenotype. Studies have indicated that GPR52 couples to Gas/olf- G proteins to activate adenylyl cyclase and modulate cAMP signaling and displays high levels of constitutive activity. Thus, GPR52 signaling via cAMP could oppose activity of D2 signaling in the striatum while stimulating the D1/N-methyl-d-aspartate (NMDA) function in the frontal cortex. Therefore, GPR52 may serve as a promising novel target for psychiatric disorders including schizophrenia and substance use disorders (SUDs).