View source for Melanocortin 1 receptor

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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 (biochemistry)|receptor]] which binds to a class of [[pituitary]] [[peptide]] [[hormone]]s known as the [[melanocortin]]s, of 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 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.

== Protein function ==
=== MC1R in mammals ===
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)|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.

=== MC1R 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 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.<ref name="pmid16704454">{{cite journal | author = Logan DW, Burn SF, Jackson IJ | title = Regulation of pigmentation in zebrafish melanophores | journal = Pigment Cell Res. | volume = 19 | issue = 3 | pages = 206–13 | year = 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]]<ref name="pmid12204775">{{cite journal | author = Aoki H, Moro O | title = Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R) | journal = Life Sci. | volume = 71 | issue = 18 | pages = 2171–9 | year = 2002 | pmid = 12204775 | doi = 10.1016/S0024-3205(02)01996-3 }}</ref><ref name="pmidunknown">{{cite journal | author = Hoek KS, Schlegel NC, Eichhoff OM, ''et al.'' | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell Melanoma Res. | volume = 21 | issue = 6 | pages = 665–76 | year = 2008| doi = 10.1111/j.1755-148X.2008.00505.x | pmid = 19067971 }}</ref>. [[Mutation]]s of the ''MC1R'' gene can either 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, while 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 (but not limited to): 

* [[laboratory mice]]<ref name="pmid8458079">{{cite journal | author = 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 = 827–834 | year = 1993 | pmid = 8458079| doi = 10.1016/0092-8674(93)90572-8 }}</ref>
* [[dog]]s<ref name="pmid10602988">{{cite journal | author = 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 = Mamm. Genome | volume = 11 | issue = 1 | pages = 24–30 | year = 2000 | pmid = 10602988 | doi = 10.1007/s003350010005 }}</ref><ref name="pmid17485734">{{cite journal | author = Schmutz SM, Berryere TG | title = The genetics of cream coat color in dogs | journal = J. Hered. | 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 | author = 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 = Curr. Biol. | volume = 13 | issue = 5 | pages = 448–53 | year = 2003 | pmid = 12620197 | doi = 10.1016/S0960-9822(03)00128-3 }}</ref> 
* [[cattle]]<ref name="pmid8535072">{{cite journal | author = 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 = Mamm. Genome | volume = 6 | issue = 9 | pages = 636–9 | year = 1995 | pmid = 8535072 | doi = 10.1007/BF00352371 }}</ref> 
* [[chicken]]s<ref name="pmid8764834">{{cite journal | author = 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 = Biochim. Biophys. Acta | volume = 1308 | issue = 2 | pages = 164–8 | year = 1996 | pmid = 8764834 | doi = | issn = }}</ref> 
* [[bananaquit]]<ref name="pmid11369199">{{cite journal | author = 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 = Curr. Biol. | volume = 11 | issue = 8 | pages = 550–7 | year = 2001 | pmid = 11369199 | doi = 10.1016/S0960-9822(01)00158-0 }}</ref> 
* [[Kermode bear]]s<ref name="pmid11566108">{{cite journal | author = Ritland K, Newton C, Marshall HD | title = Inheritance and population structure of the white-phased "Kermode" black bear | journal = Curr. Biol. | volume = 11 | issue = 18 | pages = 1468–72 | year = 2001 | pmid = 11566108 | doi = 10.1016/S0960-9822(01)00448-1 }}</ref>
* [[Rock pocket mouse|Rock pocket mice]]<ref name="pmid12704245">{{cite journal | author = Nachman MW, Hoekstra HE, D'Agostino SL | title = The genetic basis of adaptive melanism in pocket mice | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 9 | pages = 5268–73 | year = 2003 | pmid = 12704245 | doi = 10.1073/pnas.0431157100 | pmc = 154334 }}</ref>
* [[Domestic rabbit]]s<ref name="pmid16978179">{{cite journal | author = 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 = Anim. Genet. | volume = 37 | issue = 5 | pages = 489–93 | year = 2006 | pmid = 16978179 | doi = 10.1111/j.1365-2052.2006.01494.x }}</ref>

In 1995 a landmark study demonstrated that over 80% of humans with [[red hair]] or fair skin have a dysfunctional variant of the ''MC1R'' gene.<ref name="pmid7581459">{{cite journal | author = 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 = Nat. Genet. | volume = 11 | issue = 3 | pages = 328–30 | year = 1995 | pmid = 7581459 | doi = 10.1038/ng1195-328 }}</ref>

This discovery provoked interest in determining why there is an unusual prevalence of red hair and pale skin in some northern European populations, specifically [[Great Britain|Britain]] and [[Ireland]]. The [[Single-origin hypothesis|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 an active ''MC1R'' variant and, accordingly, darker hair and skin (as displayed by indigenous Africans today). Concordant with the migration north, the selective pressure maintaining dark skin decreased as radiation from the sun became less intense. Thus variations in ''MC1R'' began to appear in the human population, resulting in the paler skin and red hair of some Europeans. 

[[File:Unlabeled Renatto Luschan Skin color map.png|right|thumb|300px|[[Human skin color]] map, demonstrating the prevalence of pale skin in northern [[latitude]]s. Data for native populations collected by R. Biasutti prior to 1940]]

Studies find no evidence for [[Directional selection|positive selection]] driving these changes. Instead, the absence of high levels of [[solar radiation]] in northern Europe relaxed the [[Selection|selective pressure]] on active ''MC1R'', allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by [[genetic drift]].<ref name="pmid10733465">{{cite journal | author = 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 = Am. J. Hum. Genet. | volume = 66 | issue = 4 | pages = 1351–61 | year = 2000 | pmid = 10733465 | doi = 10.1086/302863 | pmc = 1288200 }}</ref>

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.<ref>{{cite web |url = http://www.ananova.com/news/story/sm_80720.html |title = Scottish redheads 'more sexually attractive' |accessdate = 2007-10-31 |author = |date = |publisher = Ananova }}</ref>

== A role outside pigmentation ==
{{As of|2005|alt=Recent}} experiments by researchers at [[McGill University]], [[Montreal]], [[Canada]] with 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 [[analgetic]]s.<ref name="pmid15994880">{{cite journal | author = 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 = J. Med. Genet. | volume = 42 | issue = 7 | pages = 583–7 | year = 2005 | pmid = 15994880 | doi = 10.1136/jmg.2004.027698 | pmc = 1736101 }}</ref>

This work strongly suggests a role for MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known.

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

== References ==
{{reflist|2}}

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

== Further reading ==
* {{cite book | author = Roach, Marion | title = Roots of Desire: The Myth, Meaning and Sexual Power of Red Hair | publisher = Bloomsbury USA | location = | year = 2005 | pages = 256 pages | isbn = 1-58234-344-6 | oclc = | doi = }}
* {{cite web |url = http://www.wellcome.ac.uk/en/genome/genesandbody/hg07f002.html |title = The roots of red hair |accessdate = 2007-10-31 |author = Rees, Jonathan |date = 2003 |publisher = Wellcome Trust }}
* {{cite book | author = Silvers, Willys K. | title = The Coat Colors of Mice | publisher = Springer-Verlag | location = | year = 1979 | pages = | isbn = 0-387-90367-4}}

* {{cite web |url = http://www.informatics.jax.org/wksilvers/| title = The Coat Colors of Mice | author = Silvers, Willys K. | date = 2003| publisher = Mouse Genome Informatics}}

Millington GWM. (2006) Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 31: 407-412.

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