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Letters to Nature

Nature 371, 799-802 (27 October 1994) | doi:10.1038/371799a0; Accepted 15 September 1994

Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor

Dongsi Lu*, Derril Willard†, Indravadan R. Patel†, Sue Kadwell†, Laurie Overton†, Tom Kost†, Michael Luther†, Wenbiao Chen*, Richard P. Woychik‡, William O. Wilkison†§ & Roger D. Cone*

  1. *Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland, Oregon 97201, USA
  2. †Division of Molecular Sciences, Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA
  3. ‡Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-8077, USA
  4. §To whom correspondence should be addressed.
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THE genetic loci agouti and extension control the relative amounts of eumelanin (brown–black) and phaeomelanin (yellow–red) pigments in mammals1: extension encodes the receptor for melano-cyte-stimulating hormone (MSH)2 and agouti encodes a novel 131-amino-acid protein containing a signal sequence3,4. Agouti, which is produced in the hair follicle5, acts on follicular melanocytes6 to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur. Here we use partially purified agouti protein to demonstrate that agouti is a high-affinity antagonist of the MSH receptor and blocks alpha-MSH stimulation of adenylyl cyclase, the effector through which alpha-MSH induces eumelanin synthesis. Agouti was also found to be an antagonist of the melanocortin-4 receptor7,8, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse9 may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.