 | CUTANEOUS NEUROIMMUNOMODULATION: THE PROOPIOMELANOCORTIN SYSTEM
Copyright © 1999 by the New York Academy of Sciences
description
Annals of the New York Academy of Sciences 885:143-152 (1999)
© 1999 New York Academy of Sciences
Molecular Pharmacology of Agouti Protein in Vitro and in Vivo
GREGORY S. BARSHa,
MICHAEL M. OLLMANN,
BRENT D. WILSON,
KIMBERLY A. MILLER AND
TERESA M. GUNN
Departments of Pediatrics and Genetics, and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA
aAddress for Correspondence: Greg Barsh, Beckman Center B271A, Stanford University School of Medicine, Stanford, CA 94305-5323, USA. 650-723-5035 (voice); 650-723-1399 (fax); gbarsh{at}cmgm.stanford.edu (e-mail).
Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from  -MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxy-terminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby -MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.
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