title: Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor.
abstract: 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.
authors.affiliation: Vollum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland 97201.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.forename: D
authors.initials: D
authors.lastname: Willard
authors.forename: I R
authors.initials: IR
authors.lastname: Patel
authors.forename: S
authors.initials: S
authors.lastname: Kadwell
authors.forename: L
authors.initials: L
authors.lastname: Overton
authors.forename: T
authors.initials: T
authors.lastname: Kost
authors.forename: M
authors.initials: M
authors.lastname: Luther
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: R P
authors.initials: RP
authors.lastname: Woychik
authors.forename: W O
authors.initials: WO
authors.lastname: Wilkison
mesh_terms: 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
chemical_list: 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