Melanocortin 1 receptor

Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
Identifiers
Symbols	MC1R ; CMM5; MSH-R; SHEP2
External IDs	OMIM: 155555 MGI: 99456 HomoloGene: 1789 IUPHAR: 282 ChEMBL: 3795 GeneCards: MC1R Gene
Gene ontology Molecular function • melanocortin receptor activity • melanocyte-stimulating hormone receptor activity • protein binding • G-protein coupled peptide receptor activity • ubiquitin protein ligase binding • hormone binding Cellular component • intracellular • plasma membrane • integral component of plasma membrane Biological process • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • multicellular organismal development • UV protection • positive regulation of protein kinase A signaling • sensory perception of pain • positive regulation of cAMP biosynthetic process • negative regulation of tumor necrosis factor production • intracellular signal transduction • melanin biosynthetic process • pigmentation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of protein kinase B signaling • UV-damage excision repair • positive regulation of protein kinase C signaling • positive regulation of feeding behavior Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4157	17199
Ensembl	ENSG00000258839	ENSMUSG00000074037
UniProt	Q01726	Q01727
RefSeq (mRNA)	NM_002386	NM_008559
RefSeq (protein)	NP_002377	NP_032585
Location (UCSC)	Chr 16: 89.91 – 89.92 Mb	Chr 8: 123.41 – 123.41 Mb
PubMed search

The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). MC1R is one of the key proteins involved in regulating mammalian skin and hair color. It is located on the plasma membrane of specialized cells known as melanocytes, which produce the pigment melanin through the process of melanogenesis. It works by controlling the type of melanin being produced, and its activation causes the melanocyte to switch from generating the yellow or red phaeomelanin by default to the brown or black eumelanin in replacement.

Function

In mammals and humans

The MC1R protein lies within the cell membrane, and is signalled by melanocyte-stimulating hormone (MSH) released by the pituitary gland.^[1] When activated by one of the variants of MSH, typically α-MSH, MC1R initiates a complex signaling cascade that leads to the production of the brown or black pigment eumelanin. In contrast, the receptor can also be antagonized by agouti signalling peptide (ASIP), which reverts the cell back to producing the yellow or red phaeomelanin.

The pulsatile nature of ASIP signalling through MC1R produces the characteristic yellow and black agouti banding pattern observed on most mammalian hair. In some species, ASIP signaling is not of a pulsative nature, but is limited to certain regions. This is especially conspicuous in horses, where a bay horse has black legs, mane, and tail, but a reddish body. A notable exception to this is human hair, which is neither banded nor particoloured, so is thought to be regulated by α-MSH signaling through MC1R exclusively.

In the United States, about 25% of the population carries the mutated melanocortin 1 receptor that causes red hair. With one in four people as carriers, the chance of two people having a child with red hair is about 2% (one in 64).^[2] The prevalence of red hair varies considerably worldwide.

In mutant yellow-orange mice and human redheads, both with nonfunctional MC1R, both genotypes display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to morphine-metabolite analgesics.^[3] These observations suggest a role for mammalian MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known. People with freckles and no red hair have an 85% chance of carrying the MC1R gene that is connected to red hair. People with no freckles and no red hair have an 18% chance of carrying the MC1R gene linked to red hair.^[4]

Ligands

Agonists

• α-MSH - nonselective peptide full agonist
• β-MSH - nonselective peptide full agonist
• γ-MSH - nonselective peptide full agonist
• ACTH - nonselective peptide full agonist
• Afamelanotide - nonselective peptide full agonist
• BMS-470,539 - selective small-molecule full agonist
• Bremelanotide - nonselective peptide full agonist
• Melanotan II - nonselective peptide full agonist
• Modimelanotide - nonselective peptide full agonist
• Setmelanotide - nonselective peptide full agonist

Antagonists

• Agouti signalling peptide - nonselective peptide antagonist

In other organisms

Zebrafish MC1R mediates the response of fish chromatophores on exposure to dark (top), in comparison to light (bottom), environments.

MC1R has a slightly different function in cold-blooded animals such as fish, amphibians, and reptiles. Here, α-MSH activation of MC1R results in the dispersion of eumelanin-filled melanosomes throughout the interior of pigment cells (called melanophores). This gives the skin of the animal a darker hue and often occurs in response to changes in mood or environment. Such a physiological color change implicates MC1R as a key mediator of adaptive cryptic coloration. The role of ASIP's binding to MC1R in regulating this adaptation is unclear; however, in teleost fish at least, functional antagonism is provided by melanin-concentrating hormone. This signals through its receptor to aggregate the melanosomes toward a small area in the centre of the melanophore, resulting in the animal's having a lighter overall appearance.^[5] Cephalopods generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented chromatophores. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these invertebrates.

Pigmentation genetics

MC1R gene expression is regulated by the microphthalmia-associated transcription factor (MITF).^[6][7] Mutations of the MC1R gene either can create a receptor that constantly signals, even when not stimulated, or can lower the receptor's activity. Alleles for constitutively active MC1R are inherited dominantly and result in a black coat colour, whereas alleles for dysfunctional MC1R are recessive and result in a light coat colour. Variants of MC1R associated with black, red/yellow, and white/cream coat colors in numerous animal species have been reported, including:

• Laboratory mice^[8]
• Dogs^[9][10]
• Big cats^[11]
• Horses^[12]
• Cattle^[13]
• Chickens^[14]
• Bananaquit^[15]
• Gyrfalcon^[16]
• Kermode bears^[17]
• Rock pocket mice^[18]
• Domestic rabbits^[19]

A study on unrelated British and Irish individuals demonstrated that over 80% of people with red hair and/or fair skin that tan poorly have a dysfunctional variant of the MC1R gene. This is compared to less than 20% in people with brown or black hair, and less than 4% in people showing a good tanning response.^[4]

The Out-of-Africa model proposes that modern humans originated in Africa and migrated north to populate Europe and Asia. These migrants most likely had a functional MC1R variant and, accordingly, dark hair and skin as displayed by indigenous Africans today. As humans migrated north, the absence of high levels of solar radiation in northern Europe and Asia relaxed the selective pressure on active MC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift.^[20] Studies show the MC1R Arg163Gln allele has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations.^[21] No evidence is known for positive selection of MC1R alleles in Europe^[22] and no evidence of an association between MC1R and the evolution of light skin in European populations.^[23]

See also

• Chromatophore
• Melanocyte
• SLC24A5
• Melanin
• Pigment
• Human skin color
• Freckles
• Melanotropin receptor

References

1. Online 'Mendelian Inheritance in Man' (OMIM) 155555
2. "The Red Hair Polymorphisms". Retrieved 20 July 2013.
3. Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, Dahan A (2005). "Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans". J. Med. Genet. 42 (7): 583–7. doi:10.1136/jmg.2004.027698. PMC 1736101. PMID 15994880.
4. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ (1995). "Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans". Nat. Genet. 11 (3): 328–30. doi:10.1038/ng1195-328. PMID 7581459.
5. Logan DW, Burn SF, Jackson IJ (2006). "Regulation of pigmentation in zebrafish melanophores". Pigment Cell Res. 19 (3): 206–13. doi:10.1111/j.1600-0749.2006.00307.x. PMID 16704454.
6. Aoki H, Moro O (2002). "Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R)". Life Sci. 71 (18): 2171–9. doi:10.1016/S0024-3205(02)01996-3. PMID 12204775.
7. Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
8. Robbins LS; Nadeau JH; Johnson KR; Kelly MA; Roselli-Rehfuss L; Baack E; Mountjoy KG; Cone RD (1993). "Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function.". Cell 72 (6): 827–834. doi:10.1016/0092-8674(93)90572-8. PMID 8458079.
9. Newton JM, Wilkie AL, He L, Jordan SA, Metallinos DL, Holmes NG, Jackson IJ, Barsh GS (2000). "Melanocortin 1 receptor variation in the domestic dog". Mamm. Genome 11 (1): 24–30. doi:10.1007/s003350010005. PMID 10602988.
10. Schmutz SM, Berryere TG (2007). "The genetics of cream coat color in dogs". J. Hered. 98 (5): 544–8. doi:10.1093/jhered/esm018. PMID 17485734.
11. Eizirik E, Yuhki N, Johnson WE, Menotti-Raymond M, Hannah SS, O'Brien SJ (2003). "Molecular genetics and evolution of melanism in the cat family". Curr. Biol. 13 (5): 448–53. doi:10.1016/S0960-9822(03)00128-3. PMID 12620197.
12. "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation". Hmg.oxfordjournals.org. Retrieved 2013-04-01.
13. Klungland H, Våge DI, Gomez-Raya L, Adalsteinsson S, Lien S (1995). "The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination". Mamm. Genome 6 (9): 636–9. doi:10.1007/BF00352371. PMID 8535072.
14. Takeuchi S, Suzuki H, Yabuuchi M, Takahashi S (1996). "A possible involvement of melanocortin 1-receptor in regulating feather color pigmentation in the chicken". Biochim. Biophys. Acta 1308 (2): 164–8. doi:10.1016/0167-4781(96)00100-5. PMID 8764834.
15. Theron E, Hawkins K, Bermingham E, Ricklefs RE, Mundy NI (2001). "The molecular basis of an avian plumage polymorphism in the wild: a melanocortin-1-receptor point mutation is perfectly associated with the melanic plumage morph of the bananaquit, Coereba flaveola". Curr. Biol. 11 (8): 550–7. doi:10.1016/S0960-9822(01)00158-0. PMID 11369199.
16. Johnson JA, Ambers AD, Burnham KK (2012). "Genetics of plumage color in the Gyrfalcon (Falco rusticolus): analysis of the melanocortin-1 receptor gene". J. Hered. 103 (3): 315–21. doi:10.1093/jhered/ess023. PMID 22504110.
17. Ritland K, Newton C, Marshall HD (2001). "Inheritance and population structure of the white-phased "Kermode" black bear". Curr. Biol. 11 (18): 1468–72. doi:10.1016/S0960-9822(01)00448-1. PMID 11566108.
18. Nachman MW, Hoekstra HE, D'Agostino SL (2003). "The genetic basis of adaptive melanism in pocket mice". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5268–73. doi:10.1073/pnas.0431157100. PMC 154334. PMID 12704245.
19. Fontanesi L, Tazzoli M, Beretti F, Russo V (2006). "Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus)". Anim. Genet. 37 (5): 489–93. doi:10.1111/j.1365-2052.2006.01494.x. PMID 16978179.
20. Jablonski NG, Chaplin G (5 May 2010). "Colloquium Paper: Human skin pigmentation as an adaptation to UV radiation". Proceedings of the National Academy of Sciences 107 (Supplement_2): 8962–8968. doi:10.1073/pnas.0914628107. PMC 3024016. PMID 20445093.
21. Peng S, Lu XM, Luo HR, Xiang-Yu JG, Zhang YP (March 2001). "Melanocortin-1 receptor gene variants in four Chinese ethnic populations". Cell Res. 11 (1): 81–4. doi:10.1038/sj.cr.7290070. PMID 11305330.
22. Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, Rees JL (2000). "Evidence for variable selective pressures at MC1R". Am. J. Hum. Genet. 66 (4): 1351–61. doi:10.1086/302863. PMC 1288200. PMID 10733465.
23. Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD (March 2007). "Genetic evidence for the convergent evolution of light skin in Europeans and East Asians". Mol. Biol. Evol. 24 (3): 710–22. doi:10.1093/molbev/msl203. PMID 17182896.

Further reading

• Roach, Marion (2005). Roots of Desire: The Myth, Meaning and Sexual Power of Red Hair. Bloomsbury USA. pp. 256 pages. ISBN 1-58234-344-6.
• Rees, Jonathan (2003). "The roots of red hair". Wellcome Trust. Archived from the original on 2007-10-30. Retrieved 2007-10-31.
• Silvers, Willys K. (1979). The Coat Colors of Mice. Springer-Verlag. ISBN 0-387-90367-4.
• Silvers, Willys K. (2003). "The Coat Colors of Mice". Mouse Genome Informatics.
• Millington GW (May 2006). "Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors". Clin. Exp. Dermatol. 31 (3): 407–12. doi:10.1111/j.1365-2230.2006.02128.x. PMID 16681590.

External links

• "Melanocortin Receptors: MC₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Melanocortin Receptor 1 at the US National Library of Medicine Medical Subject Headings (MeSH)