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

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 α-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 α-MSH stimulation of adenylyl cyclase, the effector through which α-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.

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