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Molecular characterization of the melanin-concentrating-hormone receptor

Nature volume 400, pages 265–269 (1999)Cite this article

Abstract

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 molecules1. 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 receptors2,3. We show that the natural ligand of this receptor is the neuropeptide melanin-concentrating hormone (MCH)4. MCH is a cyclic peptide that regulates a variety of functions in the mammalian brain, in particular feeding behaviour5,6. We demonstrate that nanomolar concentrations of MCH strongly activate SLC-1-related pathways through Gαi and/or Gαq 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.

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Figure 1: Purification of SLC-1 endogenous ligand from rat brain extracts.
Figure 2: Specificity of the interaction between MCH and SLC-1.
Figure 3: Regional distribution of SLC-1 mRNA.

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Acknowledgements

We thank S. Rattan and S. Merten for technical assistance; C. Li for making stable cell lines at the initial stage; Y. Chen for in situ hybridization; V. H. Cao and A. Henschen–Edman for mass spectrometry and sequence analysis; F. Monsma and R. Henningsen for chimaeric G-protein constructs; D. Piomelli and Q.-Y. Zhou for critical reading of the manuscript; and B. O'Dowd for discussions on orphan receptors. This work was supported by a grant from Hoffman-La Roche and by the Eric L. and Lila D. Nelson Chair in Neuropharmacology.

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Author notes

  1. Yumiko Saito, Hans-Peter Nothacker and Olivier Civelli: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Irvine, 92697-4625, California, USA

    Yumiko Saito, Hans-Peter Nothacker, Zhiwei Wang, Steven H. S. Lin, Frances Leslie & Olivier Civelli

  2. Department of Anatomy and Neurobiology, Irvine, 92697-4625, California, USA

    Frances Leslie

  3. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, 92697-4625, California, USA

    Olivier Civelli

Authors
  1. Yumiko Saito
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Correspondence to Olivier Civelli.

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Saito, Y., Nothacker, HP., Wang, Z. et al. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265–269 (1999). https://doi.org/10.1038/22321

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