Melanocortin 1 receptor (MC1R) as a global regulator of cutaneous UV responses: Molecular interactions and opportunities for melanoma prevention

Abstract

UV radiation is a pervasive environmental agent that affects the skin in complex ways Melanocortin 1 receptor (MC1R). It benefits human health by its contribution to the biosynthesis of vitamin D in the skin, however it also is a major carcinogen responsible for millions of skin cancers diagnosed each year. One of the most important physiologic responses recruited with UV exposure is the melanocortin signaling axis. This pathway, initiated by melanocortins such as melanocyte stimulating hormone (α-MSH) or adrenocorticotropic hormone (ACTH), is dependent on the signaling function of the melanocortin 1 receptor (MC1R), a Gs protein-coupled cell surface receptor found on melanocytes in the skin. MC1R mediates its downstream UV-protective responses through activation of adenylyl cyclase and production of the second messenger cAMP. In melanocytes, cAMP stimulation leads to improved survival and UV-defensive sequelae. Here, we review how MC1R signaling protects melanocytes from UV-induced malignant degeneration, focusing on recent insights into molecular links between MC1R signaling and the nucleotide excision repair (NER) genome maintenance pathway. Finally, we highlight how insights into the MC1R UV protective response may facilitate the development of rational melanoma -protective strategies.