Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R

Melanin-concentrating hormone (MCH) is a 19-aa cyclic neuropeptide original ly isolated from chum salmon pituitaries. Besides its effects on the aggreg ation of melanophores in fish several lines of evidence suggest that in mam mals MCH functions as a regulator of energy homeostasis. Recently, several groups reported the identification of an orphan G protein-coupled receptor as a receptor for MCH (MCH-1R). We hereby report the identification of a se cond human MCH receptor termed MCH-2R, which shares about 38% amino acid id entity with MCH-1R. MCH-2R displayed high-affinity MCH binding, resulting i n inositol phosphate turnover and release of intracellular calcium in mamma lian cells. In contrast to MCH-1R, MCH-2R signaling is not sensitive to per tussis toxin and MCH-2R cannot reduce forskolin-stimulated cAMP production, suggesting an exclusive G(alphaq) coupling of the MCH-2R in cell-based sys tems. Northern blot and in situ hybridization analysis of human and monkey tissue shows that expression of MCH-2R mRNA is restricted to several region s of the brain, including the arcuate nucleus and the ventral medial hypoth alamus, areas implicated in regulation of body weight. In addition, the hum an MCH-2R gene was mapped to the long arm of chromosome 6 at band 6q16.2-16 .3, a region reported to be associated with cytogenetic abnormalities of ob ese patients. The characterization of a second mammalian G protein-coupled receptor for MCH potentially indicates that the control of energy homeostas is in mammals by the MCH neuropeptide system may be more complex than initi ally anticipated.