Asp10 in Lys gamma2 MSH determines selective activation of the melanocortin MC3 receptor

Abstract

The melanocortin MC3 and MC4 receptors are the main melanocortin receptors expressed in brain. Of the endogenous melanocortins, 2-melanocortin stimulating hormone (MSH) selectively activates the melanocortin MC3 receptor, whereas - and -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-2-MSH for the melanocortin MC3 receptor versus the melanocortin MC4 receptor. Introduction of Asp10 into [Nle4]-MSH as in [Nle4,Gly5,Asp10]-MSH selectively increased the EC50 value for the melanocortin MC4 receptor. Conversely, removal of Asp10, as in [Nle4,Gly10]Lys-2-MSH, selectively decreased the EC50 value for the melanocortin MC4 receptor. Thus, Asp10 in Lys-2-MSH determined selectivity for the melanocortin MC3 receptor versus the melanocortin MC4 receptor.