Molecular characterization of the melanin-concentrating-hormone receptor.
Orphan G-protein-coupled receptors (GPCRs) are cloned proteins with structural characteristics common to the GPCRs but that bind unidentified ligands. Orphan GPCRs have been used as targets to identify novel transmitter molecules. Here we describe the isolation from brain extracts and the characterization of the natural ligand of a particular orphan GPCR (SLC-1) that is sequentially homologous to the somatostatin receptors. We show that the natural ligand of this receptor is the neuropeptide melanin-concentrating hormone (MCH). MCH is a cyclic peptide that regulates a variety of functions in the mammalian brain, in particular feeding behaviour. We demonstrate that nanomolar concentrations of MCH strongly activate SLC-1-related pathways through G(alpha)i and/or G(alpha)q proteins. We have analysed the tissue localization of the MCH receptor and find that it is expressed in several brain regions, in particular those involved in olfactory learning and reinforcement mechanisms, indicating that therapies targeting the MCH receptor should act on the neuronal regulation of food consumption.
Saito
Y
Y
Department of Pharmacology, University of California, Irvine 92697-4625, USA.
Nothacker
H P
HP
Wang
Z
Z
Lin
S H
SH
Leslie
F
F
Civelli
O
O
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005247:Feeding Behavior / Q000502:physiology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007028:Hypothalamic Hormones / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D008543:Melanins / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D010907:Pituitary Hormones / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012474:Salmon; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection
D007028:Hypothalamic Hormones; D008024:Ligands; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; D008543:Melanins; D010907:Pituitary Hormones; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; C019463:melanin-concentrating hormone; D019204:GTP-Binding Proteins