Melanocortin 1 Receptor: Structure, Function, and Regulation

Abstract

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts NER.

The melanoma‐linked “redhead” MC1R influences dopaminergic neuron survival

“…14 Intracellular MC1R undergoes oligomerization, which can significantly affect its signaling. 6 It is unclear whether a band at higher molecular weight in both brain tissues and cells that appears to respond modestly to shRNA represents MC1R oligomers. Further characterization of MC1R subcellular distribution and oligomerization would be helpful in deciphering regulation of its function in the SN dopaminergic neurons.…”

“…A cyclic adenosine monophosphate-stimulating Gprotein-coupled receptor (GPCR), melanocortin 1 receptor (MC1R) contributes to the regulation of skin physiology through the melanin synthetic pathway as well as pigmentation-independent mechanisms. 5,6 Loss-offunction variants of MC1R in humans are associated with red hair and fair skin and increased risk of developing melanoma. 7,8 In mice, an inactivating mutation of MC1R (MC1R extension, e/e) with a phenotype analogous to red hair/fair skin in humans, 9 results in impaired skin protection and is sufficient to enhance melanoma formation.…”

Melanocortin receptor agonists MCR1‐5 protect photoreceptors from high‐glucose damage and restore antioxidant enzymes in primary retinal cell culture

“…In fact, photoreceptor cell membranes are particularly rich in polyunsaturated fatty acids and extremely vulnerable to oxidative damage being the major site of superoxide generation in diabetes [34]. As MCR 1,5 modulate the nuclear transcription of the cAMP response element-binding protein (CREB) [17,35] and CREB as a redox-regulated pathway modulating MnSOD transcription [36], a possible theoretical frame, supporting this proposal, is that high-glucose exposure overexpresses MCR 1,5 and the addition of MCR 1,5 agonists lead to cAMP-PKA-CREB, increasing MnSOD transcription.…”

Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma

“…Patients’ age, tannability, nevus numbers, freckling, and UV exposure have been associated with melanoma molecular subtypes, particularly those defined by somatic driver mutations in BRAF and NRAS (Hacker et al, 2010, Hacker et al, 2013, Hacker et al, 2016, Liu et al, 2007, Thomas et al, 2007, Wu et al, 2014). MC1R , the melanocortin 1 receptor, controls melanin production, pigmentation phenotypes, and influences sun sensitivity and melanoma risk (Wolf Horrell et al, 2016). MC1R germline variants were associated with BRAF + melanomas in studies in Italy and San Francisco (Fargnoli et al, 2008, Landi et al, 2006) but not in North Carolina or Australia (Hacker et al, 2010, Hacker et al, 2016, Thomas et al, 2010b), while the association was restricted to head and neck melanomas in a study from Spain and Austria (Hacker et al, 2013).…”