Molecular pharmacology of Agouti protein in vitro and in vivo.
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 alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.
Barsh
G S
GS
Department of Pediatrics, Stanford University School of Medicine, California, USA. gbarsh@cmgm.stanford.edu
Ollmann
M M
MM
Wilson
B D
BD
Miller
K A
KA
Gunn
T M
TM
D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D000818:Animals; D006200:Hair Color / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018043:Receptors, Corticotropin / Q000502:physiology; D044101:Receptors, Melanocortin; D015398:Signal Transduction; D000521:alpha-MSH / Q000037:antagonists & inhibitors / Q000502:physiology*
D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C515183:a protein, mouse; D000521:alpha-MSH