G protein-coupled receptor 135 (GPR135)

G protein-coupled receptor 135 (GPR135) is an orphan receptor—meaning its endogenous ligand is unknown and it does not bind melatonin or other well-characterized ligands[2][5]. It belongs to the G protein-coupled receptor (GPCR) superfamily and is highly evolutionarily conserved across vertebrates, indicating likely physiological importance[1][2][3]. GPR135 is abundantly expressed in the brain and also found in tissues such as pancreatic beta cells[1][2][4]. Functionally, GPR135 is distinguished by its spontaneous, agonist-independent recruitment of beta-arrestins, while it is largely silent on canonical G protein-mediated signaling pathways (Gs/cAMP, Gi/o/cAMP, and Gq/IP1)[2][5][7]. This marked beta-arrestin-biased signaling may be relevant to models of GPCR function and pharmacology. GPR135 can also form heteromeric complexes with the melatonin MT2 receptor, affecting MT2-mediated signaling in a reciprocal regulatory manner, but has not been directly linked to any specific diseases or known drug interactions[2][5]. Comprehensive disease roles, biomarkers, and safety issues remain uncharacterized.

Other names

GPR135HUMNPIIY20probable G-protein coupled receptor 135

Beta-arrestin pathway recruitment (spontaneous, ligand-independent)[2][5]