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 mammals: extension encodes the receptor for melanocyte-stimulating hormone (MSH) and agouti encodes a novel 131-amino-acid protein containing a signal sequence. Agouti, which is produced in the hair follicle, acts on follicular melanocytes 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 receptor, a related MSH-binding receptor. Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle.
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Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201.
Willard
D
D
Patel
I R
IR
Kadwell
S
S
Overton
L
L
Kost
T
T
Luther
M
M
Chen
W
W
Woychik
R P
RP
Wilkison
W O
WO
D000262:Adenylyl Cyclases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D054366:Agouti Signaling Protein; D000818:Animals; D016367:Baculoviridae; D002417:Cattle; D002460:Cell Line; D004789:Enzyme Activation; D006197:Hair / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D009765:Obesity / Q000209:etiology; D011506:Proteins / Q000502:physiology*; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
C515182:ASIP protein, human; D054366:Agouti Signaling Protein; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011979:Receptors, Pituitary Hormone; D011994:Recombinant Proteins; C515183:a protein, mouse; C029446:MSH receptor; D000324:Adrenocorticotropic Hormone; D000262:Adenylyl Cyclases