Agouti antagonism of melanocortin-4 receptor: Greater effect with desacetyl-alpha-melanocyte-stimulating hormone (MSH) than with alpha-MSH

Desacetyl-alpha-MSH is more abundant than alpha-MSH in the brain, the fetus , human blood, and amniotic fluid, but there is little information on its a bility to interact with melanocortin receptors. The aim of this study is to compare and contrast the ability of desacetyl-alpha-MSH and alpha-MSH to c ouple melanocortin receptors stably expressed in HEK293 cells, to the prote in kinase A (PKA) signaling pathway. Desacetyl-alpha-MSH activated mouse MC 1, MC3, MC4 and MC5 receptors with EC(50)s = 0.13, 0.96, 0.53, and 0.84 nM, and alpha-MSH activated these receptors with EC(50)s = 0.17, 0.88, 1.05, a nd 1.34 nM, respectively. Mouse agouti protein competitively antagonized al pha-MSH and desrtcetyl-alpha-MSH coupling to the MC1-R similarly. In contra st, mouse agouti protein antagonized desacetyl-alpha-MSH much more effectiv ely and potently than alpha-MSH coupling the MC4-R to the PKA signaling pat hway. Furthermore, mouse agouti protein (10 nM) significantly reduced (1.4- fold) the maximum response of mMC4-R to desacetyl-alpha-MSH and 100 nM mous e agouti significantly increased (4.8-fold) the EC50. Minimal antagonism of alpha-MSH coupling mMC4-R to the PKA signaling pathway was observed with 1 0 nhl mouse agouti, whereas both 50 and 100 nM mouse agouti appeared to red uce the maximum reponse (1.1- and 1.3-fold, respectively) and increase the EC50 (2.5 and 3.4-fold respectively). Mouse agouti protein did not signific antly antagonize either alpha-MSH or desacetyl-alpha-MSH coupling mouse MC3 and MC5 receptors. Understanding the similarities and differences in activ ation of melanocortin receptors by desacetyl-alpha-MSH and alpha-MSH will c ontribute to delineating the functional roles for these endogenous melanoco rtin peptides.