Melanocortin‐1 receptor structure and functional regulation

Abstract

SummaryThe melanogenic actions of the melanocortins are mediated by the melanocortin-1 receptor (MC1R). MC1R is a member of the G-protein-coupled receptors (GPCR) superfamily expressed in cutaneous and hair follicle melanocytes. Activation of MC1R by adrenocorticotrophin or a-melanocyte stimulating hormone is positively coupled to the cAMP signaling pathway and leads to a stimulation of melanogenesis and a switch from the synthesis of pheomelanins to the production of eumelanic pigments. The functional behavior of the MC1R agrees with emerging concepts in GPCR signaling including dimerization, coupling to more than one signaling pathway and a high agonist-independent constitutive activity accounting for inverse agonism phenomena. In addition, MC1R displays unique properties such as an unusually high number of natural variants often associated with clearly visible phenotypes and the occurrence of endogenous peptide antagonists. Therefore MC1R is an ideal model to study GPCR function. Here we review our current knowledge of MC1R structure and function, with emphasis on information gathered from the analysis of natural variants. We also discuss recent data on the regulation of MC1R function by paracrine and endocrine factors and by external stimuli such as ultraviolet light.

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

“…1g) to reveal that MC1R is palmitoylated (Extended Data Fig. 1h), consistent with integral membrane proteins G protein-coupled receptors (GPCRs) like MC1R 9 being palmitoylated during activation. Palmitoylation site prediction (NBA-palm) analysis 21 highlighted MC1R Cysteines 78 and 315 as potential palmitoylation sites (Extended Data Fig.…”

“…Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) 9 stimulates cAMP signaling and melanin production and enhances DNA repair after UV irradiation (UVR) 10–16 . Individuals carrying MC1R variants, especially those associated with red hair color, fair skin and poor tanning ability (RHC-variants), are associated with higher risk of melanoma 5,17,18,19,20 .…”

Mouse coat color mutations: From fancy mice to functional genomics

“…The wild-type mouse has agouti coat color; the hair is banded where the tip has black eumelanin, the center has pheomelanin and the base again eumelanin. These bands of pigment are generated by pigment type switching, which is regulated primarily by the melanocortin-1 receptor (Mc1r) and its ligands, ␣-melanocyte-stimulating hormone (␣-MSH) and the agouti signal protein (ASP; reviewed by Schaffer andBolognia, 2001, Wolff, 2003;Garcia-Borron et al, 2005). These proteins are encoded by the extension (e, now Mc1r, also known as recessive yellow), pro-opiomelanocortin-1 (Pomc1), and agouti (a) coat color loci, respectively.…”

Fear of Pain Mediates the Association between MC1R Genotype and Dental Fear

“…Ultimately, participants were assigned to 1 of 2 groups based on the number of variant alleles present: those with normal genotype had zero risk alleles, and those with variant genotype had ≥1 risk alleles. This method for establishing participant MC1R variant status was utilized because it matches that employed by Binkley and colleagues (2009), which the current study aimed to replicate, and because variations at study SNPs have been shown to be associated with loss of function (García-Borrón et al 2005).…”

“…MC1R variant status was determined for participants by combining genetic data across 6 single-nucleotide polymorphisms (SNPs) to calculate a risk score (i.e., the number of risk alleles present for each participant was calculated; see Appendix for method). Risk alleles at these 6 SNPs are missense (coding) variants responsible for amino acid residue changes that are predicted to be deleterious to protein function (García-Borrón et al 2005). Ultimately, participants were assigned to 1 of 2 groups based on the number of variant alleles present: those with normal genotype had zero risk alleles, and those with variant genotype had ≥1 risk alleles.…”