Identification and characterization of a melanin-concentrating hormone receptor

Melanin-concentrating hormone (MCH), a neuropeptide expressed in central and peripheral nervous systems, plays an important role in the control of feeding behaviors and energy metabolism. An orphan G protein-coupled receptor (SLC-1/GPR24) has recently been identified as a receptor for MCH (MCHR1). We report here the identification and characterization of a G protein-coupled receptor as the MCH receptor subtype 2 (MCHR2). MCHR2 has higher protein sequence homology to MCHR1 than any other G protein-coupled receptor. The expression of MCHR2 has been detected in many regions of the brain. In contrast to MCHR1, which is intronless in the coding region and is located at the chromosomal locus 22q13.3, the MCHR2 gene has multiple exons and is mapped to locus 6q21. MCHR2 is specifically activated by nanomolar concentrations of MCH, binds to MCH with high affinity, and signals through Gq protein. This discovery is important for a full understanding of MCH biology and the development of potential therapeutics for diseases involving MCH, including obesity.

[1]  S. Coughlin,et al.  Thrombin-induced events in non-platelet cells are mediated by the unique proteolytic mechanism established for the cloned platelet thrombin receptor , 1992, The Journal of cell biology.

[2]  C. Wilson,et al.  α-Melanocyte-Stimulating Hormone (α-MSH) and Melanin-Concentrating Hormone (MCH) Modify Monoaminergic Levels in the Preoptic Area of the Rat , 1997, Peptides.

[3]  M. I. Gonzalez,et al.  Behavioral effects of α-MSH and MCH after central administration in the female rat , 1996, Peptides.

[4]  B. Cheatham,et al.  Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes. , 2000, Diabetes.

[5]  W. Moolenaar.  Development of Our Current Understanding of Bioactive Lysophospholipids , 2000, Annals of the New York Academy of Sciences.

[6]  J. Vaughan,et al.  The melanin‐concentrating hormone system of the rat brain: An immuno‐ and hybridization histochemical characterization , 1992, The Journal of comparative neurology.

[7]  E. Grazzini,et al.  The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor , 1999, Nature Cell Biology.

[8]  P. Casey,et al.  Signalling functions and biochemical properties of pertussis toxin-resistant G-proteins. , 1997, The Biochemical journal.

[9]  Pierre Baldi,et al.  Hidden Markov Models of the G-Protein-Coupled Receptor Family , 1994, J. Comput. Biol..

[10]  P. Sawchenko,et al.  The rat melanin-concentrating hormone messenger ribonucleic acid encodes multiple putative neuropeptides coexpressed in the dorsolateral hypothalamus. , 1989, Endocrinology.

[11]  Yumiko Saito,et al.  Molecular characterization of the melanin-concentrating-hormone receptor , 1999, Nature.

[12]  B. Lowell,et al.  Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. , 2001, The Journal of clinical investigation.

[13]  J. Keefer,et al.  Differential targeting and retention of G protein-coupled receptors in polarized epithelial cells. , 1997, Journal of receptor and signal transduction research.

[14]  Clifford B. Saper,et al.  Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat , 1984, Brain Research Reviews.

[15]  E. Bolewska-Pedyczak,et al.  Immunosuppressive activity in the series of cycloamanide peptides from mushrooms , 1993, Peptides.

[16]  B. Baker,et al.  Melanin-Concentrating Hormone (MCH) Antagonizes the Effects of α-MSH and Neuropeptide E-I on Grooming and Locomotor Activities in the Rat , 1997, Peptides.

[17]  D. Jacobowitz,et al.  Immunohistochemical localization of a melanin concentrating hormone-like peptide in the rat brain , 1985, Brain Research Bulletin.

[18]  J. Chambers,et al.  Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1 , 1999, Nature.

[19]  O. Civelli,et al.  Melanin-concentrating Hormone Receptor: An Orphan Receptor Fits the Key , 2000, Trends in Endocrinology & Metabolism.

[20]  A. Eberle,et al.  Melanin‐concentrating hormone binding to mouse melanoma cells in vitro , 1995, FEBS letters.

[21]  H. Kawauchi,et al.  Characterization of melanin-concentrating hormone in chum salmon pituitaries , 1983, Nature.

[22]  O. Nishimura,et al.  Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. , 1999, Biochemical and biophysical research communications.

[23]  D. Richter,et al.  Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin‐like receptor 1 (SLC‐1) , 1999, FEBS letters.

[24]  V Hachinski,et al.  Vascular Factors in Cognitive Impairment‐Where Are We Now? , 2000, Annals of the New York Academy of Sciences.

[25]  S. Gammeltoft,et al.  A role for melanin-concentrating hormone in the central regulation of feeding behaviour , 1996, Nature.

[26]  O. Prospero-Garcia,et al.  A cortical neuropeptide with neuronal depressant and sleep-modulating properties , 1996, Nature.

[27]  S. Rees,et al.  A bioluminescent assay for agonist activity at potentially any G-protein-coupled receptor. , 1997, Analytical biochemistry.

[28]  J. Bittencourt,et al.  The rat melanin-concentrating hormone gene encodes an additional putative protein in a different reading frame. , 1996, Endocrinology.

[29]  L. F. Kolakowski,et al.  Characterization of a human gene related to genes encoding somatostatin receptors , 1996, FEBS letters.

[30]  M. A. McClure,et al.  Hidden Markov models of biological primary sequence information. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Wess,et al.  Structural basis of receptor/G protein coupling selectivity studied with muscarinic receptors as model systems. , 1997, Life sciences.

[32]  B. Lowell,et al.  Mice lacking melanin-concentrating hormone are hypophagic and lean , 1998, Nature.

[33]  D. Jezova,et al.  Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier. , 1992, Endocrinology.

[34]  P. Bickford,et al.  Alpha-MSH and MCH are functional antagonists in a CNS auditory gating paradigm , 1993, Peptides.

[35]  C. Saper,et al.  Cholecystokinin-immunoreactive innervation of the ventromedial hypothalamus in the rat: Possible substrate for autonomic regulation of feeding , 1985, Neuroscience Letters.

[36]  L. Slieker,et al.  Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain. , 2001, Endocrinology.

[37]  P. Maycox,et al.  The distribution of the mRNA and protein products of the melanin‐concentrating hormone (MCH) receptor gene, slc‐1, in the central nervous system of the rat , 2000, The European journal of neuroscience.

[38]  Jean Martinez,et al.  Melanin-concentrating hormone binding sites in human SVK14 keratinocytes. , 1997, Biochemical and biophysical research communications.

[39]  B. Hawes,et al.  The melanin-concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. , 2000, Endocrinology.