Melanocortin 1 receptor

2017-11-04T02:36:27Z

2602:306:C4BA:E270:4177:9510:C275:E59E: /* Some roles in development */

{{Infobox_gene}}
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 hormone]]s known as the [[melanocortin]]s, which include [[adrenocorticotropic hormone]] (ACTH) and the different forms of [[melanocyte-stimulating hormone]] (MSH).

MC1R is one of the key [[protein]]s involved in regulating [[mammalian]] [[Human skin color|skin]] and [[Human hair color|hair color]]. It is located on the [[Cell membrane|plasma membrane]] of specialized [[Cell (biology)|cell]]s known as [[melanocyte]]s, which produce the [[Biological pigment|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.

MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes and susceptibilty to infections and pain.

== Functions ==

=== Coloration in mammals ===
The MC1R protein lies within the [[cell membrane]], and is signalled by [[melanocyte-stimulating hormone]] (MSH) released by the [[pituitary]] gland.<ref name=OMIMMC1R>{{OMIM|155555}}</ref> 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)|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).<ref>{{Cite web|url = http://www.myredhairgene.com/page3/page3.html|title = The Red Hair Polymorphisms|accessdate = 20 July 2013}}</ref> The prevalence of [[red hair]] varies considerably worldwide. 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.<ref name="pmid7581459" />

=== Pain in mammals ===

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 [[analgesic]]s.<ref name="pmid15994880">{{cite journal | vauthors = Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, Dahan A | title = Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans | journal = Journal of Medical Genetics | volume = 42 | issue = 7 | pages = 583–7 | date = July 2005 | pmid = 15994880 | pmc = 1736101 | doi = 10.1136/jmg.2004.027698 }}</ref> 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.

In a certain genetic background in mice it has been reported that animals lacking MC1R had increased tolerance to [[capsaicin]] acting through the [[TRPV1]] receptor and decreased response to chemically induced inflammatory pain.<ref>{{cite journal | vauthors = Delaney A, Keighren M, Fleetwood-Walker SM, Jackson IJ | title = Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin | journal = PLoS One | volume = 5 | issue = 9 | pages = e12498 | date = September 2010 | pmid = 20856883 | doi = 10.1371/journal.pone.0012498 | pmc=2938350}}</ref>

Humans with MC1R mutations have been reported to need approximately 20% more [[Inhalational anaesthetic]] than controls.<ref>{{cite journal | vauthors = Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG, Veauthier JM, Loyd G, Sessler DI | title = Anesthetic requirement is increased in redheads | journal = Anesthesiology | volume = 101 | issue = 2 | pages = 279–83 | date = August 2004 | pmid = 15277908 | pmc = 1362956 | doi=10.1097/00000542-200408000-00006}}</ref> [[Lidocaine]] was reported to be much less effective in reducing pain in another study of humans with MC1R mutations<ref>{{cite journal | vauthors = Liem EB, Joiner TV, Tsueda K, Sessler DI | title = Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads | journal = Anesthesiology | volume = 102 | issue = 3 | pages = 509–14 | date = March 2005 | pmid = 15731586 | pmc = 1692342 | doi=10.1097/00000542-200503000-00006}}</ref>
[[File:MCR1erythro4TC.jpg|thumb|Model of melanocortin receptors and erythropoiesis]]

=== Some roles in development ===

Since [[G protein–coupled receptor]]s are known to activate [[Signal transduction]] in cells, it should not be surprising to find MC1R involved in development. As one example at the cellular level, preventing signalling by MC1R stopped [[erythropoiesis]] from proceeding from the polychromatic cell stage (poly-E in the figure) to the orthochromatic cell stage (ortho-E in the diagram).<ref>{{cite journal | vauthors = Simamura E, Arikawa T, Ikeda T, Shimada H, Shoji H, Masuta H, Nakajima Y, Otani H, Yonekura H, Hatta T | title = Melanocortins contribute to sequential differentiation and enucleation of human erythroblasts via melanocortin receptors 1, 2 and 5 | journal = PLoS One | volume = 10 | issue = 4 | pages = e0123232 | date = 2015 | pmid = 25860801 | doi = 10.1371/journal.pone.0123232 | pmc=4393082}}</ref> The same report showed that neutralizing [[Antibody|antibodies]] to MC1R prevented phosphorylation of [[STAT5]] by [[erythropoietin]], and that MC2R and MC5R were also involved, as shown in their model.

[[File:MCR1carti4TC.jpg|thumb|MC1R deficiency and osteoarthritis]]
One example at the tissue level showed the involvement of MC1R in the normal and pathological development of [[articular cartilage]] in the mouse [[knee]].<ref>{{cite journal | vauthors = Lorenz J, Seebach E, Hackmayer G, Greth C, Bauer RJ, Kleinschmidt K, Bettenworth D, Böhm M, Grifka J, Grässel S | title = Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis | journal = PLoS One | volume = 9 | issue = 9 | pages = e105858 | date = 2014 | pmid = 25191747 | doi = 10.1371/journal.pone.0105858 | pmc=4156302}}</ref> In this study the authors compared normal mice with mice completely lacking MC1R. Even without experimental induction of osteoarthritis, mice without MC1R had less articular cartilage (as shown by the red staining in the image). After experimental induction of osteoarthritis, the defect caused by MC1R was more pronounced.

=== MC1R and infection/inflammation ===

The involvement of MC1R in a rat model of [[Candida albicans]] [[vaginitis]] was investigated.<ref>{{cite journal | vauthors = Ji HX, Zou YL, Duan JJ, Jia ZR, Li XJ, Wang Z, Li L, Li YW, Liu GY, Tong MQ, Li XY, Zhang GH, Dai XR, He L, Li ZY, Cao C, Yang Y | title = The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization | journal = PLoS One | volume = 8 | issue = 2 | pages = e56004 | date = 2013 | pmid = 23457491 | doi = 10.1371/journal.pone.0056004 | pmc=3573073}}</ref> These authors suggest that MC1R is important in anti-fungal and anti-inflammatory processes, in part because [[siRNA]] knockdown of MC1R almost completely prevented the responses.

[[Nosocomial infections]] are of variable importance. One of the most important is complicated [[sepsis]], which was defined as sepsis with organ dysfunction. One variant of MC1R (MC1RR163Q, rs885479) was reported to be associated with lowered risk of developing complicated sepsis during hospitalization after trauma.<ref>{{cite journal | vauthors = Seaton ME, Parent BA, Sood RF, Wurfel MM, Muffley LA, O'Keefe GE, Gibran NS | title = Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study | journal = Shock | volume = 47 | issue = 1 | pages = 79–85 | date = January 2017 | pmid = 27488084 | doi = 10.1097/SHK.0000000000000708 | pmc=5167637}}</ref> Thus, if the association is confirmed, MC1R targeting may become a therapeutic option to prevent severe sepsis.

=== Role in cancer independent of skin color ===

MC1R signalling stimulates [[antioxidant]] and [[DNA repair]] pathways, as reviewed.<ref>{{cite journal | vauthors = Maresca V, Flori E, Picardo M | title = Skin phototype: a new perspective | journal = Pigment Cell & Melanoma Research | volume = 28 | issue = 4 | pages = 378–89 | date = July 2015 | pmid = 25786343 | doi = 10.1111/pcmr.12365 }}</ref><ref name = Feller2016 /> There are [[single nucleotide polymorphisms]] in MC1R that are associated with predisposition to nonmelanoma skin cancer.<ref>{{cite journal | vauthors = Binstock M, Hafeez F, Metchnikoff C, Arron ST | title = Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review | journal = The British Journal of Dermatology | volume = 171 | issue = 4 | pages = 713–21 | date = October 2014 | pmid = 25319428 | doi = 10.1111/bjd.13283 }}</ref>
It has been reported that variants of MC1R, even in [[heterozygotes]] and independent of their effects on pigmentation, are risk factors for [[basal cell carcinoma]] and [[squamous cell carcinoma]]<ref>{{cite journal | vauthors = Box NF, Duffy DL, Irving RE, Russell A, Chen W, Griffyths LR, Parsons PG, Green AC, Sturm RA | title = Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma | journal = The Journal of Investigative Dermatology | volume = 116 | issue = 2 | pages = 224–9 | date = February 2001 | pmid = 11179997 | doi = 10.1046/j.1523-1747.2001.01224.x }}</ref> A review has discussed the role of some MC1R variants in [[melanoma]] and basal and squamous cell carcinomas independent of pigment production.<ref name = Feller2016>{{cite journal | vauthors = Feller L, Khammissa RA, Kramer B, Altini M, Lemmer J | title = Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face | journal = Head & Face Medicine | volume = 12 | pages = 11 | date = February 2016 | pmid = 26850723 | doi = 10.1186/s13005-016-0106-0 | pmc=4744388}}</ref>

=== Role in kidney pathology ===
[[Membranous glomerulonephritis]] is a serious human disease that can be teated with [[ACTH]], which is a known [[Melanocortin 1 receptor#Agonists|agonist of MC1R]]. In a rat model of nephritis it was found that treatment with a different [[agonist]] of MC1R improved aspects of kidney morphology and reduced [[proteinuria]],<ref name="pmid20507942">{{cite journal | vauthors = Lindskog A, Ebefors K, Johansson ME, Stefánsson B, Granqvist A, Arnadottir M, Berg AL, Nyström J, Haraldsson B | title = Melanocortin 1 receptor agonists reduce proteinuria | journal = Journal of the American Society of Nephrology : JASN | volume = 21 | issue = 8 | pages = 1290–8 | year = 2010 | pmid = 20507942 | pmc = 2938589 | doi = 10.1681/ASN.2009101025 }}</ref><ref name="pmid24498203">{{cite journal | vauthors = Lindskog Jonsson A, Granqvist A, Elvin J, Johansson ME, Haraldsson B, Nyström J | title = Effects of melanocortin 1 receptor agonists in experimental nephropathies | journal = PLOS ONE | volume = 9 | issue = 1 | pages = e87816 | year = 2014 | pmid = 24498203 | pmc = 3907561 | doi = 10.1371/journal.pone.0087816 }}</ref> which may help explain the benefit of ACTH in humans.

== Ligands ==

=== Agonists ===
* [[alpha-Melanocyte-stimulating hormone|α-MSH]] - nonselective peptide full agonist
* [[beta-Melanocyte-stimulating hormone|β-MSH]] - nonselective peptide full agonist
* [[gamma-Melanocyte-stimulating hormone|γ-MSH]] - nonselective peptide full agonist
* [[Adrenocorticotropic hormone|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 ===
[[File:Zfishchroma.jpg|thumb|150px|[[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 [[Poikilotherm|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 [[melanophore]]s). 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.<ref name="pmid16704454">{{cite journal | vauthors = Logan DW, Burn SF, Jackson IJ | title = Regulation of pigmentation in zebrafish melanophores | journal = Pigment Cell Research | volume = 19 | issue = 3 | pages = 206–13 | date = June 2006 | pmid = 16704454 | doi = 10.1111/j.1600-0749.2006.00307.x }}</ref> [[Cephalopod]]s generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented [[chromatophore]]s. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these [[invertebrate]]s.

== Pigmentation genetics ==
''MC1R'' [[gene]] expression is regulated by the [[microphthalmia-associated transcription factor]] (MITF).<ref name="pmid12204775">{{cite journal | vauthors = Aoki H, Moro O | title = Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R) | journal = Life Sciences | volume = 71 | issue = 18 | pages = 2171–9 | date = September 2002 | pmid = 12204775 | doi = 10.1016/S0024-3205(02)01996-3 }}</ref><ref name="pmidunknown">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–76 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x }}</ref> [[Mutation]]s of the ''MC1R'' gene either can create a [[Receptor (biochemistry)|receptor]] that constantly signals, even when not stimulated, or can lower the receptor's activity. [[Allele]]s for constitutively active ''MC1R'' are inherited [[Dominant gene|dominantly]] and result in a black coat colour, whereas alleles for dysfunctional ''MC1R'' are [[Recessive gene|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]]<ref name="pmid8458079">{{cite journal | vauthors = Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD | title = Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function | journal = Cell | volume = 72 | issue = 6 | pages = 827–34 | date = March 1993 | pmid = 8458079 | doi = 10.1016/0092-8674(93)90572-8 }}</ref>
* [[Dog]]s<ref name="pmid10602988">{{cite journal | vauthors = Newton JM, Wilkie AL, He L, Jordan SA, Metallinos DL, Holmes NG, Jackson IJ, Barsh GS | title = Melanocortin 1 receptor variation in the domestic dog | journal = Mammalian Genome | volume = 11 | issue = 1 | pages = 24–30 | date = January 2000 | pmid = 10602988 | doi = 10.1007/s003350010005 }}</ref><ref name="pmid17485734">{{cite journal | vauthors = Schmutz SM, Berryere TG | title = The genetics of cream coat color in dogs | journal = The Journal of Heredity | volume = 98 | issue = 5 | pages = 544–8 | year = 2007 | pmid = 17485734 | doi = 10.1093/jhered/esm018 }}</ref>
* [[Big cat]]s<ref name="pmid12620197">{{cite journal | vauthors = Eizirik E, Yuhki N, Johnson WE, Menotti-Raymond M, Hannah SS, O'Brien SJ | title = Molecular genetics and evolution of melanism in the cat family | journal = Current Biology | volume = 13 | issue = 5 | pages = 448–53 | date = March 2003 | pmid = 12620197 | doi = 10.1016/S0960-9822(03)00128-3 }}</ref>
* [[Horses]]<ref name=Flanagan>{{cite journal | vauthors = Flanagan N, Healy E, Ray A, Philips S, Todd C, Jackson IJ, Birch-Machin MA, Rees JL | title = Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation | journal = Human Molecular Genetics | volume = 9 | issue = 17 | pages = 2531–7 | year = 2000 | pmid = 11030758 | doi = 10.1093/hmg/9.17.2531 }}</ref>
* [[Cattle]]<ref name="pmid8535072">{{cite journal | vauthors = Klungland H, Våge DI, Gomez-Raya L, Adalsteinsson S, Lien S | title = The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination | journal = Mammalian Genome | volume = 6 | issue = 9 | pages = 636–9 | date = September 1995 | pmid = 8535072 | doi = 10.1007/BF00352371 }}</ref>
* [[Chicken]]s<ref name="pmid8764834">{{cite journal | vauthors = Takeuchi S, Suzuki H, Yabuuchi M, Takahashi S | title = A possible involvement of melanocortin 1-receptor in regulating feather color pigmentation in the chicken | journal = Biochimica et Biophysica Acta | volume = 1308 | issue = 2 | pages = 164–8 | date = August 1996 | pmid = 8764834 | doi = 10.1016/0167-4781(96)00100-5 }}</ref>
* [[Bananaquit]]<ref name="pmid11369199">{{cite journal | vauthors = Theron E, Hawkins K, Bermingham E, Ricklefs RE, Mundy NI | title = 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 | journal = Current Biology | volume = 11 | issue = 8 | pages = 550–7 | date = April 2001 | pmid = 11369199 | doi = 10.1016/S0960-9822(01)00158-0 }}</ref>
* [[Gyrfalcon]]<ref name="pmid22504110">{{cite journal | vauthors = Johnson JA, Ambers AD, Burnham KK | title = Genetics of plumage color in the Gyrfalcon (Falco rusticolus): analysis of the melanocortin-1 receptor gene | journal = The Journal of Heredity | volume = 103 | issue = 3 | pages = 315–21 | year = 2012 | pmid = 22504110 | doi = 10.1093/jhered/ess023 }}</ref>
* [[Kermode bear]]s<ref name="pmid11566108">{{cite journal | vauthors = Ritland K, Newton C, Marshall HD | title = Inheritance and population structure of the white-phased "Kermode" black bear | journal = Current Biology | volume = 11 | issue = 18 | pages = 1468–72 | date = September 2001 | pmid = 11566108 | doi = 10.1016/S0960-9822(01)00448-1 }}</ref>
* [[Rock pocket mouse|Rock pocket mice]]<ref name="pmid12704245">{{cite journal | vauthors = Nachman MW, Hoekstra HE, D'Agostino SL | title = The genetic basis of adaptive melanism in pocket mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 9 | pages = 5268–73 | date = April 2003 | pmid = 12704245 | pmc = 154334 | doi = 10.1073/pnas.0431157100 }}</ref>
* [[Domestic rabbit]]s<ref name="pmid16978179">{{cite journal | vauthors = Fontanesi L, Tazzoli M, Beretti F, Russo V | title = Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus) | journal = Animal Genetics | volume = 37 | issue = 5 | pages = 489–93 | date = October 2006 | pmid = 16978179 | doi = 10.1111/j.1365-2052.2006.01494.x }}</ref>
*[[Antarctic fur seal]]s<ref>{{cite journal | vauthors = Peters L, Humble E, Kröcker N, Fuchs B, Forcada J, Hoffman JI | title = Born blonde: a recessive loss-of-function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals | journal = Ecology and Evolution | volume = 6 | issue = 16 | pages = 5705–17 | date = August 2016 | pmid = 27547348 | pmc = 4983585 | doi = 10.1002/ece3.2290 }}</ref>
*[[Mammoth]]<ref>{{cite journal | vauthors = Römpler H, Rohland N, Lalueza-Fox C, Willerslev E, Kuznetsova T, Rabeder G, Bertranpetit J, Schöneberg T, Hofreiter M | title = Nuclear gene indicates coat-color polymorphism in mammoths | journal = Science | volume = 313 | issue = 5783 | pages = 62 | date = July 2006 | pmid = 16825562 | doi = 10.1126/science.1128994 }}</ref>

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.<ref name="pmid7581459">{{cite journal | vauthors = Valverde P, Healy E, Jackson I, Rees JL, Thody AJ | title = Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans | journal = Nature Genetics | volume = 11 | issue = 3 | pages = 328–30 | date = November 1995 | pmid = 7581459 | doi = 10.1038/ng1195-328 }}</ref>

The [[Single-origin hypothesis|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 [[Selection (biology)|selective pressure]] on active ''MC1R'', allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by [[genetic drift]].<ref>{{cite journal | vauthors = Jablonski NG, Chaplin G | title = Colloquium paper: human skin pigmentation as an adaptation to UV radiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 Suppl 2 | issue = Supplement_2 | pages = 8962–8 | date = May 2010 | pmid = 20445093 | pmc = 3024016 | doi = 10.1073/pnas.0914628107 }}</ref> 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.<ref>{{cite journal | vauthors = Peng S, Lu XM, Luo HR, Xiang-Yu JG, Zhang YP | title = Melanocortin-1 receptor gene variants in four Chinese ethnic populations | journal = Cell Research | volume = 11 | issue = 1 | pages = 81–4 | date = March 2001 | pmid = 11305330 | doi = 10.1038/sj.cr.7290070 }}</ref> No evidence is known for [[Directional selection|positive selection]] of ''MC1R'' alleles in Europe<ref name="pmid10733465">{{cite journal | vauthors = Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, Rees JL | title = Evidence for variable selective pressures at MC1R | journal = American Journal of Human Genetics | volume = 66 | issue = 4 | pages = 1351–61 | date = April 2000 | pmid = 10733465 | pmc = 1288200 | doi = 10.1086/302863 }}</ref> and there is no evidence of an association between ''MC1R'' and the evolution of light skin in European populations.<ref>{{cite journal | vauthors = Norton HL, Kittles RA, Parra E, McKeigue P, Mao X, Cheng K, Canfield VA, Bradley DG, McEvoy B, Shriver MD | title = Genetic evidence for the convergent evolution of light skin in Europeans and East Asians | journal = Molecular Biology and Evolution | volume = 24 | issue = 3 | pages = 710–22 | date = March 2007 | pmid = 17182896 | doi = 10.1093/molbev/msl203 }}</ref> The lightening of skin color in Europeans and East Asians is an example of [[Convergent evolution#Primates|convergent evolution]].

== See also ==
* [[Chromatophore]]
* [[Melanocyte]]
* [[SLC24A5]]
* [[Melanin]]
* [[Pigment]]
* [[Human skin color]]
* [[Freckles]]
* [[Melanotropin receptor]]

== References ==
{{Reflist|2}}

== Further reading ==
{{Refbegin}}
* {{cite book | title = Roots of Desire: The Myth, Meaning and Sexual Power of Red Hair | publisher = Bloomsbury USA | year = 2005 | isbn = 1-58234-344-6 | location = | pages = 256 pages | doi = | oclc = | author = Roach, Marion }}
* {{cite web|url=http://www.wellcome.ac.uk/en/genome/genesandbody/hg07f002.html |title=The roots of red hair |year=2003 |publisher=Wellcome Trust |accessdate=2007-10-31 |author=Rees, Jonathan |archiveurl=https://web.archive.org/web/20071030211630/http://www.wellcome.ac.uk/en/genome/genesandbody/hg07f002.html |archivedate=2007-10-30 |deadurl=yes |df= }}
* {{cite book | title = The Coat Colors of Mice | publisher = Springer-Verlag | year = 1979 | isbn = 0-387-90367-4| location = | pages = | author = Silvers, Willys K. }}
* {{cite web |url = http://www.informatics.jax.org/wksilvers/| title = The Coat Colors of Mice | year = 2003| publisher = Mouse Genome Informatics| author = Silvers, Willys K. }}
* {{cite journal | vauthors = Millington GW | title = Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors | journal = Clinical and Experimental Dermatology | volume = 31 | issue = 3 | pages = 407–12 | date = May 2006 | pmid = 16681590 | doi = 10.1111/j.1365-2230.2006.02128.x }}
{{Refend}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2348 | title = Melanocortin Receptors: MC<sub>1</sub> | accessdate = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | quote = }}
* {{MeshName|Melanocortin+Receptor+1}}

{{G protein-coupled receptors}}
{{Hair colors}}
{{Melanocortin receptor modulators}}

{{DEFAULTSORT:Melanocortin 1 Receptor}}
[[Category:G protein coupled receptors]]
[[Category:Human proteins]]
[[Category:Hair color]]
[[Category:Skin pigmentation]]
[[Category:Mutated genes]]
[[Category:Genes on human chromosome 16]]

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Melanocortin 1 receptor