Melanocortin 1 receptor

Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
Identifiers
Symbols	MC1R; CMM5; MGC14337; MSH-R; SHEP2
External IDs	OMIM: 155555 MGI: 99456 HomoloGene: 1789 GeneCards: MC1R Gene
Gene Ontology Molecular function • receptor activity • melanocortin receptor activity • melanocyte-stimulating hormone receptor activity • protein binding • peptide receptor activity, G-protein coupled • ubiquitin protein ligase binding Cellular component • plasma membrane • plasma membrane • plasma membrane • integral to plasma membrane Biological process • G-protein signaling, coupled to cyclic nucleotide second messenger • intracellular protein kinase cascade • multicellular organismal development • UV protection • positive regulation of protein kinase A signaling cascade • positive regulation of cAMP biosynthetic process • negative regulation of tumor necrosis factor production • pigmentation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of protein kinase B signaling cascade • UV-damage excision repair • positive regulation of protein kinase C signaling cascade Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4157	17199
Ensembl	ENSG00000198211	ENSMUSG00000074037
UniProt	Q01726	Q75NA2
RefSeq (mRNA)	NM_002386	NM_008559.2
RefSeq (protein)	NP_002377	NP_032585.2
Location (UCSC)	Chr 16: 88.51 – 88.51 Mb	Chr 8: 125.93 – 125.93 Mb
PubMed search	[1]	[2]

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 which binds to a class of pituitary peptide hormones known as the melanocortins, of 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 a process referred to as 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

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 signaling peptide (ASIP), which reverts the cell back to producing the yellow or red phaeomelanin.

The pulsatile nature of ASIP signaling 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, and thus is thought to be regulated by α-MSH signaling through MC1R exclusively.

In mutant yellow-orange mice and human redheads, both with non-functional MC1R, show that both genotypes display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to morphine-metabolite analgetics.^[2] These observations suggests a role for mammalian MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known.

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 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 towards a small area in the centre of the melanophore, resulting in the animal having a lighter overall appearance.^[3] 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.^[4][5] Mutations of the MC1R gene can either 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, while 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 (but not limited to):

• laboratory mice^[6]
• dogs^[7][8]
• big cats^[9]
• cattle^[10]
• chickens^[11]
• bananaquit^[12]
• Kermode bears^[13]
• Rock pocket mice^[14]
• Domestic rabbits^[15]

A study on unrelated British and Irish individuals demonstrated that over 80% of people with red hair and/or fair skin that tans poorly have a dysfunctional variant of the MC1R gene. This is compared to less than 20% in brown or black haired people, and less than 4% in people showing a good tanning response.^[16]

This discovery provoked interest in determining why there is an unusual prevalence of red hair and non-tanning skin in some northern European populations, specifically Britain and Ireland. The Out-of-Africa model proposes that modern humans originated in Africa and migrated north to populate Europe and Asia. It is most likely that these migrants 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. Studies show the MC1R Arg163Gln allelle has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations.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.  of MC1R allelles in Europe^[17] and no evidence of an association between MC1R and the evolution of light skin in European populations.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. 

The reason for the unusually high numbers of dysfunctional MC1R variants in certain human populations is not yet known, though sexual selection for red hair has been proposed.^[18]

See also

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

References

1. ^ Online 'Mendelian Inheritance in Man' (OMIM) 155555
2. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1736101. 
3. ^ 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. 
4. ^ 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. 
5. ^ 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. 
6. ^ 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. 
7. ^ 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. 
8. ^ 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. 
9. ^ 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. 
10. ^ 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. 
11. ^ 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. PMID 8764834. 
12. ^ 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. 
13. ^ 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. 
14. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=154334. 
15. ^ 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. 
16. ^ 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. 
17. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1288200. 
18. ^ "Scottish redheads 'more sexually attractive'". Ananova. http://www.ananova.com/news/story/sm_80720.html. Retrieved 2007-10-31. 

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. http://web.archive.org/web/20071030211630/http://www.wellcome.ac.uk/en/genome/genesandbody/hg07f002.html. 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. http://www.informatics.jax.org/wksilvers/. 
• 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. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2348. 
• MeSH Melanocortin+Receptor+1