Asp¹⁰ in Lys-γ₂-MSH determines selective activation of the melanocortin MC₃ receptor

The melanocortin MC₃ and MC₄ receptors are the main melanocortin receptors expressed in brain. Of the endogenous melanocortins, γ₂-melanocortin stimulating hormone (MSH) selectively activates the melanocortin MC₃ receptor, whereas α- and β-MSH activate all melanocortin receptors. The aim was to gain an insight into the contribution of amino acids in positions 5 and 10 of melanocortins to the selectivity of [Nle⁴]Lys-γ₂-MSH for the melanocortin MC₃ receptor versus the melanocortin MC₄ receptor. Introduction of Asp¹⁰ into [Nle⁴]α-MSH as in [Nle⁴,Gly⁵,Asp¹⁰]α-MSH selectively increased the EC₅₀ value for the melanocortin MC₄ receptor. Conversely, removal of Asp¹⁰, as in [Nle⁴,Gly¹⁰]Lys-γ₂-MSH, selectively decreased the EC₅₀ value for the melanocortin MC₄ receptor. Thus, Asp¹⁰ in Lys-γ₂-MSH determined selectivity for the melanocortin MC₃ receptor versus the melanocortin MC₄ receptor. Copyright (C) 1998 Elsevier Science B.V.