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Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1

Author

Listed:
  • Jon Chambers

    (Departments of Molecular Screening Technologies)

  • Robert S. Ames

    (Departments of Molecular Biology)

  • Derk Bergsma

    (Departments of Molecular Biology)

  • Alison Muir

    (Departments of Molecular Screening Technologies)

  • Laura R. Fitzgerald

    (Renal Pharmacology,)

  • Guillaume Hervieu

    (Neuroscience, New Frontiers Science Park)

  • George M. Dytko

    (Renal Pharmacology,)

  • James J. Foley

    (Pulmonary Pharmacology)

  • John Martin

    (Protein Biochemistry)

  • Wu-Schyong Liu

    (Protein Biochemistry)

  • Janet Park

    (Departments of Molecular Screening Technologies)

  • Catherine Ellis

    (Departments of Molecular Biology)

  • Subinay Ganguly

    (Gene Expression Sciences SmithKline Beecham Pharmaceuticals)

  • Susan Konchar

    (Gene Expression Sciences SmithKline Beecham Pharmaceuticals)

  • Jane Cluderay

    (Neuroscience, New Frontiers Science Park)

  • Ron Leslie

    (Neuroscience, New Frontiers Science Park)

  • Shelagh Wilson

    (Departments of Molecular Screening Technologies)

  • Henry M. Sarau

    (Pulmonary Pharmacology)

Abstract

The underlying causes of obesity are poorly understood but probably involve complex interactions between many neurotransmitter and neuropeptide systems involved in the regulation of food intake and energy balance. Three pieces of evidence indicate that the neuropeptide melanin-concentrating hormone (MCH) is an important component of this system. First, MCH stimulates feeding when injected directly into rat brains1,2; second, the messenger RNA for the MCH precursor is upregulated in the hypothalamus of genetically obese mice and in fasted animals1; and third, mice lacking MCH eat less and are lean3. MCH antagonists might, therefore, provide a treatment for obesity. However, the development of such molecules has been hampered because the identity of the MCH receptor has been unknown until now. Here we show that the 353-amino-acid human orphan G-protein-coupled receptor SLC-1 (ref. 4) expressed in HEK293 cells binds MCH with sub-nanomolar affinity, and is stimulated by MCH to mobilize intracellular Ca2+ and reduce forskolin-elevated cyclic AMP levels. We also show that SLC-1 messenger RNA and protein is expressed in the ventromedial and dorsomedial nuclei of the hypothalamus, consistent with a role for SLC-1 in mediating the effects of MCH on feeding.

Suggested Citation

  • Jon Chambers & Robert S. Ames & Derk Bergsma & Alison Muir & Laura R. Fitzgerald & Guillaume Hervieu & George M. Dytko & James J. Foley & John Martin & Wu-Schyong Liu & Janet Park & Catherine Ellis & , 1999. "Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1," Nature, Nature, vol. 400(6741), pages 261-265, July.
    • Handle: RePEc:nat:nature:v:400:y:1999:i:6741:d:10.1038_22313
    DOI: 10.1038/22313
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    Cited by:

    1. Joram D Mul & Susanne E la Fleur & Pim W Toonen & Anthonieke Afrasiab-Middelman & Rob Binnekade & Dustin Schetters & Michel M M Verheij & Robert M Sears & Judith R Homberg & Anton N M Schoffelmeer & R, 2011. "Chronic Loss of Melanin-Concentrating Hormone Affects Motivational Aspects of Feeding in the Rat," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-13, May.
    2. Keshav S. Subramanian & Logan Tierno Lauer & Anna M. R. Hayes & Léa Décarie-Spain & Kara McBurnett & Anna C. Nourbash & Kristen N. Donohue & Alicia E. Kao & Alexander G. Bashaw & Denis Burdakov & Emil, 2023. "Hypothalamic melanin-concentrating hormone neurons integrate food-motivated appetitive and consummatory processes in rats," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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