Down-regulation of melanocortin receptor signaling mediated by the amino terminus of Agouti protein in Xenopus melanophores.

Abstract

Agouti protein and Agouti-related protein (Agrp) regulate pigmentation and body weight, respectively, by antagonizing melanocortin receptor signaling. A carboxyl-terminal fragment of Agouti protein, Ser73-Cys131, is sufficient for melanocortin receptor antagonism, but Western blot analysis of skin extracts reveals that the electrophoretic mobility of native Agouti protein corresponds to the mature full-length form, His23-Cys131. To investigate the potential role of the amino-terminal residues, we compared the function of full-length and carboxyl-terminal fragments of Agrp and Agouti protein in a sensitive bioassay based on pigment dispersion in Xenopus melanophores. We find that carboxyl-terminal Agouti protein, and all forms of Agrp tested, act solely by competitive antagonism of melanocortin action. However, full-length Agouti protein acts by an additional mechanism that is time- and temperature-dependent, depresses maximal levels of pigment dispersion, and is therefore likely to be mediated by receptor down-regulation. Apparent down-regulation is not observed for a mixture of amino-terminal and carboxyl-terminal fragments. We propose that the phenotypic effects of Agouti in vivo represent a bipartite mechanism: competitive antagonism of agonist binding by the carboxyl-terminal portion of Agouti protein and down-regulation of melanocortin receptor signaling by an unknown mechanism that requires residues in the amino terminus of the Agouti protein.

• Authors: M M Ollmann, G S Barsh
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 22 Pg. 15837-46 (May 28 1999) ISSN: 0021-9258 [Print] United States
• PMID: 10336487 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Agouti Signaling Protein
• Agouti-Related Protein
• Agrp protein, mouse
• Intercellular Signaling Peptides and Proteins
• Peptide Fragments
• Proteins
• Receptors, Corticotropin
• Receptors, Melanocortin
• Recombinant Proteins
• a protein, mouse
• alpha-MSH

Topics

• Agouti Signaling Protein
• Agouti-Related Protein
• Amino Acid Sequence
• Animals
• Binding, Competitive
• Cells, Cultured
• Down-Regulation (drug effects)
• Intercellular Signaling Peptides and Proteins
• Kinetics
• Melanophores (metabolism)
• Mice
• Molecular Sequence Data
• Peptide Fragments (pharmacology)
• Pigmentation (drug effects)
• Proteins (metabolism)
• Receptors, Corticotropin (antagonists & inhibitors, metabolism)
• Receptors, Melanocortin
• Recombinant Proteins (metabolism)
• Sequence Alignment
• Signal Transduction
• Skin (metabolism)
• Xenopus (metabolism)
• alpha-MSH (antagonists & inhibitors)