The Naturally Occurring Melanocortin Antagonist Agouti-Related Protein (AGRP) Possesses Similar and Distinct Interactions at the MC4 Receptor Compared with Melanocortin Agonist

Abstract

Agouti-related protein (AGRP) is one of two known naturally occurring antagonists of G-protein coupled receptors identified to date, is an antagonist of the melanocortin-4 receptor (MC4R), and is involved in obesity and the regulation of feeding behavior [1,2]. The agonists of the MC4R include the POMC derived peptides, particularly α-melanocyte stimulating hormone (α-MSH). The studies presented herein were performed to test the hypothesis that AGRP and oc-MSH possessed similar molecular recognition interactions with identical MC4R amino acids. In vitro mutagenesis at the MC4 receptor (23 mutations) and comparing agonist Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2, MTII [3] (I125-MTII, IC50) and antagonist (I125-AGRP) binding and functional activities (agonist EC50 and antagonist pA2) have been performed to test this hypothesis.