G protein-coupled receptor 61 (GPR61)

G protein-coupled receptor 61 (GPR61) is a class A, orphan GPCR highly expressed in the brain, notably in appetite-regulating centers such as the hypothalamus and pituitary[3][4][8]. It contains 7 transmembrane domains and signals via Gs proteins to increase intracellular cAMP[2][3][7]. GPR61 has constitutive (ligand-independent) activity, and mutational studies reveal that its N-terminal domain is essential for maintaining this basal signaling[1]. Structurally, GPR61 resembles biogenic amine receptors but lacks key residues for endogenous ligand binding, making it "orphan"[2][3]. Genomic studies link GPR61 to body weight, appetite, and metabolic phenotypes, making it a promising target for obesity and cachexia therapies[3][4][8]. Recent efforts have identified selective inverse agonists binding to an allosteric pocket, providing a framework for drug discovery and mechanistic insight[3][4][5]. GPR61's precise physiological ligands and functions remain under investigation, but its role in neuroendocrine and metabolic processes is supported by animal models and human genetic studies[7][8].

Other names

GPR61Biogenic amine receptor-like G-protein coupled receptorProbable G-protein coupled receptor 61GPCR3BALGR

Inverse agonists block constitutive Gs protein activation and cAMP production by binding to allosteric intracellular site, destabilizing the active conformation required for G-protein coupling. Reciprocal regulatory interaction with melatonin receptor MTNR1B, likely via receptor heteromerization.