GPR61 is an orphan G protein-coupled receptor that constitutively activates the Gs-alpha/cAMP signaling pathway in the absence of known endogenous ligands 1. The receptor demonstrates extensive spontaneous ligand-independent activities across multiple signaling pathways including cAMP, inositol phosphate, and β-arrestin recruitment, with spontaneous β-arrestin recruitment leading to receptor internalization in endosomal compartments 1. GPR61 undergoes N-glycosylation post-translational modification at position N12, which affects its cellular expression but is not required for cell surface localization 2. The receptor forms heteromers with melatonin receptor MT2, resulting in reciprocal regulatory interactions that inhibit melatonin-induced β-arrestin2 recruitment and decrease elevated cAMP levels 1. GPR61 shows significant disease relevance in metabolic disorders, with 34 missense mutations identified at higher frequency in severe obesity patients compared to normal populations, including loss-of-function variants like R236C that compromise Gs protein activation 3. The receptor is expressed in human hippocampus and immune cells, particularly showing elevated expression in Th17 cell subsets 2. GPR61 methylation patterns are influenced by environmental factors and may mediate effects of prenatal weather conditions on birth weight 4, suggesting roles in metabolic regulation and developmental processes.