Synergism Between Agouti Protein Fragment 91–131 and Melanin Concentrating Hormone

Abstract

Murine agouti protein (AP) is a 131-amino acid cysteine-rich peptide responsible for the induction of phaeomelanin production in melanocytes [1]. Overexpression and ubiquitous secretion of AP in mice carrying the lethal yellow Ay mutation leads to a bright yellow coat and obesity [1]. AP antagonizes α-melanocyte-stimulating hormone (α-MSH) at the melanocortin-1 receptor (MC1-R) and hence inhibits MSH-induced cAMP formation and melanin synthesis. AP was also shown to exhibit some MSH-agonist effects (e.g. receptor down-regulation) and to display the characteristics of an inverse agonist [2]. The finding that the C-terminal cysteine-rich fragment of AP is sufficient for a-MSH antagonism and the observation that AP evokes biological effects independent from α-MSH antagonism have prompted us to study the biological characteristics of a C-terminal AP fragment in assays typical for both types of action of AP. We have selected the mouse AP91_131 fragment which does not contain Val83, a crucial residue for the bioactivity of native AP. Also, we were interested in whether melanin-concentrating hormone (MCH), a physiological antagonist of a-MSH and inducer of food intake [3], exerts any synergistic effects on AP91_131 action. In a previous report, the strategy of the chemical synthesis of AP91_131 had been described [4]. Here we report the biological data obtained with this AP fragment. The salient finding is that the C-terminal part of AP mediates both antagonist and agonist activities, and that MCH potentiates the antagonist activity of AP91_131.