Melanin-concentrating hormone receptor 2 (MCHR2)

Melanin-concentrating hormone receptor 2 (MCHR2) is a G protein-coupled receptor primarily expressed in the human brain and certain peripheral tissues. It is activated by the neuropeptide melanin-concentrating hormone (MCH), leading to coupling with Gq/11 proteins and triggering intracellular calcium signaling. MCHR2 is structurally related to MCHR1, but differs in gene structure, G-protein coupling, tissue distribution, and binding-site features. Physiologically, MCHR2 is implicated in regulation of appetite, energy balance, and possibly mood and neuropsychiatric functions. MCHR2 is considered a candidate therapeutic target in obesity, metabolic syndromes, and other CNS disorders, but the absence of this receptor in rodent brains presents translational challenges for drug development[2][3][4]. Experimental MCHR2 ligands include peptides, small molecule antagonists, and agonists developed for research, though none have advanced to clinical use. While no approved drugs directly target MCHR2, a variety of peptide and small-molecule ligands (agonists and antagonists) have been studied preclinically as anti-obesity or neuropsychiatric agents, but none are in routine clinical use[3]. MCHR2 antagonism has been explored for anti-obesity effects due to its role in promoting food intake and energy storage[3]. Genetic and pharmacological studies also implicate MCHR2 in neuropsychiatric functions; disease associations include schizophrenia and certain cancers[4]. MCHR2 is present in humans and some primates but absent in rodents, complicating preclinical efficacy and toxicity studies[3]. Recent cryo-EM studies reveal MCHR2's ligand-binding mode and specific residues important for ligand selectivity and receptor activation, informing rational design of selective ligands[1][2].

Other names

GPR145SLTMCH receptor 2MCH-R2MCHR-2MCH2MCH2RG-protein coupled receptor 145GPRv17MCH-2RG protein-coupled receptor slt

Antagonists inhibit MCH binding, blocking downstream Gq-mediated Ca2+ signaling; agonists mimic MCH, activating receptor and intracellular signaling pathways. MCHR2 activation by MCH results in receptor conformational change, Gq/11 protein activation, and subsequent downstream calcium mobilization and phosphoinositide hydrolysis.