AGOUTI PROTEIN IS AN ANTAGONIST OF THE MELANOCYTE-STIMULATING-HORMONERECEPTOR

THE genetic loci agouti and extension control the relative amounts of eumelanin (brown-black) and phaeomelanin (yellow-red) pigments in mamm als(1): extension encodes the receptor for melanocyte-stimulating horm one (MSH)(2) and agouti encodes a novel 131-amino-acid protein contain ing a signal sequence(3,4). Agouti, which is produced in the hair foll icle(5), acts on follicular melanocytes(6) to inhibit alpha-MSH-induce d eumelanin production, resulting in the subterminal band of phaeomela nin often visible in mammalian fur. Here we use partially purified ago uti protein to demonstrate that agouti is a high-affinity antagonist o f the MSH receptor and blocks alpha-MSH stimulation of adenylyl cyclas e, the effector through which alpha-MSH induces eumelanin synthesis, A gouti was also found to be an antagonist of the melanocortin-4 recepto r(7,8), a related MSH-binding receptor. Consequently, the obesity caus ed by ectopic expression of agouti in the lethal yellow (A(y)) mouse(9 ) may be due to the inhibition of melanocortin reteptor(s) outside the hair follicle.