Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 13, 7564-7569, June 19, 2001
Neurobiology
Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R
Andreas W. Sailer*,,, Hideki Sano,§, Zhizhen Zeng¶, Terrence P. McDonald¶, Jie Pan*, Sheng-Shung Pong*, Scott D. Feighner*, Carina P. Tan*, Takehiro Fukami§, Hisashi Iwaasa§, Donna L. Hreniuk*, Nancy R. Morin*, Sharon J. Sadowski*, Makoto Ito§, Masahiko Ito§, Alka Bansal, Betty Ky¶, David J. Figueroa¶, Qingping Jiang¶, Christopher P. Austin¶, Douglas J. MacNeil*, Akane Ishihara§, Masaki Ihara§, Akio Kanatani§, Lex H. T. Van der Ploeg*, Andrew D. Howard*, and Qingyun Liu¶
Departments of * Metabolic Disorders and High-Throughput Screening and Automation, Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065; § Banyu-Tsukuba Research Institute Okubo 3, Tsukuba 300-2611 Japan; and ¶ Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486
Communicated by C. Thomas Caskey, Cogene Biotech Ventures, Ltd., Houston, TX, April 5, 2001 (received for review March 5, 2001)
Melanin-concentrating hormone (MCH) is a 19-aa cyclic neuropeptide originally isolated from chum salmon pituitaries. Besides its effects on the aggregation of melanophores in fish several lines of evidence suggest that in mammals 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 second human MCH receptor termed MCH-2R, which shares about 38% amino acid identity with MCH-1R. MCH-2R displayed high-affinity MCH binding, resulting in inositol phosphate turnover and release of intracellular calcium in mammalian cells. In contrast to MCH-1R, MCH-2R signaling is not sensitive to pertussis toxin and MCH-2R cannot reduce forskolin-stimulated cAMP production, suggesting an exclusive Gq coupling of the MCH-2R in cell-based systems. Northern blot and in situ hybridization analysis of human and monkey tissue shows that expression of MCH-2R mRNA is restricted to several regions of the brain, including the arcuate nucleus and the ventral medial hypothalamus, areas implicated in regulation of body weight. In addition, the human 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 obese patients. The characterization of a second mammalian G protein-coupled receptor for MCH potentially indicates that the control of energy homeostasis in mammals by the MCH neuropeptide system may be more complex than initially anticipated. |
