The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation

The cloning and characterization of the human melanocortin-1 receptor (MC1R ) and the demonstration that normal human melanocytes respond to the melano cortins, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocortico trophic hormone (ACTH), with increased proliferation and eumelanogenesis ha d put an end to a long-standing controversy about the role of melanocortins in regulating human cutaneous pigmentation. We have shown that alpha-MSH a nd ACTH bind the human MC1R with equal affinity, and are equipotent in thei r mitogenic and melanogenic effects on human melanocytes. We also showed th at the activation of the MC1R is important for the melanogenic response of human melanocytes to ultraviolet radiation (UVR). The MC1R is also the prin cipal mediator of the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its ow n ligands alpha-MSH and ACTH, as well as by UVR and endothelin-1. Recent st udies that we conducted on the expression of MC1R variants by human melanoc ytes and the implications of these variants on the function of the MC1R rev ealed the following. Human melanocytes homozygous for Arg160Trp mutation in the MC1R demonstrated a significantly reduced response to alpha-MSH. Also, this culture responded poorly to ASP and exhibited an exaggerated cytotoxi c response to UVR. Another culture, which was homozygous for Val92Met mutat ion in the MC1R, demonstrated a normal response to alpha-MSH. Heterozygous mutations that are frequently expressed in various melanocyte cultures did not disrupt MC1R function. These results begin to elucidate the significanc e of MC1R variants in the function of the receptor. Our data emphasize the significance of a normally functioning MC1R in the response of melanocytes to melanocortins. ASP, and UVR.