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.