G protein-coupled receptor 50 (GPR50)

G protein-coupled receptor 50 (GPR50) is an orphan GPCR structurally related to melatonin receptors but lacks endogenous melatonin-binding capacity[2][5]. GPR50 is expressed mainly in the central nervous system and is capable of heterodimerizing with both MT1 and MT2 melatonin receptors. This heterodimerization specifically inhibits MT1 (but not MT2) signaling by preventing melatonin binding and G protein coupling[6][4]. GPR50 is implicated in neurodevelopmental and metabolic processes, influencing energy metabolism, neurite outgrowth, and differentiation of neural progenitor cells via NOTCH and WNT/β-catenin pathways[5]. Human genetic studies link GPR50 gene variants to psychiatric disorders (bipolar disorder, depression, schizophrenia), and lipid metabolism disturbances (altered triglycerides, HDL)[2][5]. GPR50 has no known approved drugs or endogenous ligands, but its unique interactions with melatonin receptors suggest a possible role as a modulatory target, especially in neuropsychiatric or metabolic diseases[4][5][6].

Other names

Melatonin-related receptorMel1cH9GPR50MT3 (historical, nonstandard)Melatonin receptor-like 1 (MTR1L)

Heterodimerization-dependent modulation: GPR50 inhibits MT1 melatonin receptor function via constitutive heterodimerization, blocking ligand binding and G protein coupling to MT1[6][2][4].