MC1R

Melanocortin 1 receptor (MC1R) is a seven-transmembrane G protein-coupled receptor encoded by the MC1R gene. It is expressed mainly in epidermal melanocytes of the skin and hair follicles, where it mediates responses to melanocortin peptides—primarily α-melanocyte-stimulating hormone (α-MSH). Upon ligand binding, MC1R signals through the Gs protein to activate adenylyl cyclase, increasing intracellular cAMP and promoting the synthesis of eumelanin, the darker pigment that provides photoprotection.

Genetic variation in MC1R influences pigmentation. Numerous coding variants reduce receptor activity; several are strongly associated with red hair color, pale skin, freckles, and reduced tanning ability. Functional loss tends to shift melanin production toward pheomelanin (the lighter pigment), contributing to lighter coloration and greater sensitivity to ultraviolet radiation. The frequency of MC1R variants varies among different human populations.

Genomic context and related receptors: MC1R is located on chromosome 16q24.3 in humans and is part of the melanocortin receptor family, which includes MC1R through MC5R. The receptor is activated chiefly by α-MSH, a product of the POMC gene; other melanocortin peptides can modulate signaling at lower potency. In animals, MC1R signaling controls coat and feather coloration and serves as a model for pigmentary genetics.

Clinical relevance and research: MC1R variants are among the best-characterized genetic determinants of human pigmentation and are associated with cutaneous melanoma risk independent of visible pigmentation. Studies investigate MC1R signaling mechanisms, receptor trafficking, and pharmacological modulation, as well as its roles in inflammatory responses and nonpigmentary tissues. Animal and cellular models continue to elucidate its function.