Regulation of TNF-α secretion by a specific melanocortin-1 receptor peptide agonist

Abstract The lack of specific pharmacological tools has impeded the evaluation of the role of each melanocortin receptor (MCR) subtype in the myriad physiological effects of melanocortins. 154N-5 is an octapeptide (MFRdWFKPV-NH 2 ) that was first identified as an MC1R antagonist in Xenopus melanophores [J. Biol. Chem. 269 (1994) 29846]. In this manuscript, we show that 154N-5 is a specific agonist for human and murine MC1R. The peptide has negligible activity at MC3R and MC4R and is 25-fold less potent and a weak agonist at MC5R. 154N-5 was tested in both a cellular and an animal model of tumor necrosis factor-α (TNF-α) secretion. The inhibitory efficacy of 154N-5 on TNF-α secretion in both models was similar to the nonselective agonist NDP-α-melanocyte stimulating hormone (NDP-αMSH), thus, we conclude that inhibition of TNF-α secretion by melanocortin peptides is mediated by MC1R. 154N-5 is a valuable new tool for the evaluation of specific contribution of MC1R agonism to physiological and pathological processes.