Significance of the Melanocortin 1 Receptor in Regulating Human Melanocyte Pigmentation, Proliferation, and Survival

Abstract

The characterization of the melanocortin 1 receptor (MC1R) expressed on human melanocytes and the findings that certain mutations in the POMC gene or the MC1R gene result in red hair phenotype underscore the significance of melanocortins and MC1R in regulating human pigmentation. We demonstrated that human melanocytes respond to alpha-melanocortin (alpha-MSH) or ACTH with increased proliferation and melanogenesis, and to agouti signaling protein by abrogation of these effects. alpha-MSH and ACTH were equipotent and more potent than beta-MSH, and gamma-MSH was the least potent in activating the MC1R and stimulating melanogenesis and proliferation of human melanocytes. We characterized the MC1R genotype in a panel of human melanocyte cultures and identified three cultures that were homozygous for Arg160Trp, heterozygous for Arg151Cys and Asp294His, and heterozygous for Arg160Trp and Asp294His substitutions, respectively. Those cultures failed to respond to alpha-MSH with increase in cAMP levels, tyrosinase activity, or proliferation and had an exaggerated response to the cytotoxic effect of ultraviolet (UV) radiation. These loss-of-function mutations have been associated with red hair phenotype and increased risk for skin cancer. Melanocytes homozygous for Val29Met substitution in MC1R responded normally to alpha-MSH and UVB, suggesting that this variant is a polymorphism. We observed that alpha-MSH promotes human melanocyte survival by inhibiting the UV-induced apoptosis independently of melanin synthesis. This effect was absent in human melanocytes with loss of function MC1R mutations. We predict that the survival effect of alpha-MSH is caused by reduction of UV-induced DNA damage and contributes to the prevention of melanoma.

Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes

“…Melanogenesis is mediated by GPCRs, including MCR-1 and endothelin-1 receptors [42,43]. The endothelin receptor is known to be regulated by GRK2, and at least two of the closely related MCRs (MCR-2, MCR-4) are modulated by phosphorylation mediated by GRK2 [15,16,44].…”

Melanocortin-1 Receptor Signaling Markedly Induces the Expression of the NR4A Nuclear Receptor Subgroup in Melanocytic Cells

“…To this end, primary human melanocytes of defined MC1R genotypes were treated with NDP-MSH or vehicle and analyzed for NR4A induction at 1-and 3-h time points following administration. Previous reports have demonstrated the ability of wild-type consensus MC1R alleles to stimulate the cAMP pathway in response to NDP-MSH, an effect that is significantly attenuated in the context of homozygous RHC variant alleles (9,13,49). Three melanocyte strains homozygous for the wild-type MC1R exhibited a marked induction of the NR4A2 gene in response to NDP-MSH above basal levels (Fig.…”

“…Efforts over the last decade to understand the genetic basis of human pigmentary traits have revealed the melanocortin-1 receptor (MC1R) 5 as a key determinant of the wide phenotypic diversity in mammals (7)(8)(9). MC1R is a seven-transmembrane G-protein-coupled receptor that has been found to be highly polymorphic in Caucasian individuals, with a number of functional variants strongly associating with a phenotype of red hair, fair skin, and poor tanning ability often referred to as the Red Hair Color (RHC) phenotype (7).…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…In contrast, those Mc1R variants that produce weak or absent cAMP responses to MSH stimulation are associated with red/fair skin pigmentation and phototype (Kadekaro et al 2003). Downstream from cAMP activation, multiple events occur, including phosphorylation/activation of CREB/ATF1 transcription factors that, in turn, activate expression of the Mitf promoter in melanocytes (Bertolotto et al 1998; Figure 3.…”