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melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
Other data
LocusChr. 16 q24.3

The melanocortin-1 receptor (Mc1r) is one of the key proteins in regulating hair and skin color. A member of the G-protein-coupled receptor family of proteins, it functions at the surface of specialist pigment producing cells (called melanocytes) to regulate melanogenesis in mammals.

Protein function

Mammalian Mc1r

When stimulated by one of the cleavage products of proopiomelanocortin, typically α-melanocyte stimulating hormone (α-MSH), Mc1r initiates a complex signalling cascade that leads to the production of black or brown eumelanin. In most mammals, this signal can be altered by the binding of another protein to Mc1r. Agouti signalling peptide (Asip), a paracrine signalling factor, anatagonizes α-MSH activation of Mc1r and results in a switch to the production of red or yellow 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 signalling 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 signalling through Mc1r exclusively.

Non-mammalian Mc1r

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-melanocyte stimulating hormone 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. [1] 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

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):

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.[11]

This discovery provoked interest in determining why there is an unusual prevelance of red hair and pale skin in some northern European populations, specifically Scotland 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 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.

Human skin color map, demonstrating the prevelence of pale skin in northern latitudes. Data for native populations collected by R. Biasutti prior to 1940

Studies find no evidence for positive selection driving these changes. Instead, the absence of high levels of solar radiation in northern Europe relaxed the selective pressure on active Mc1r, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift.[12]

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.[13]

A role outside pigmentation

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 analgetics.[14]

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


  1. Logan D, Burn SF, Jackson I (2006). "Regulation of pigmentation in zebrafish melanophores". Pigment Cell Res. 19 (3): 206–13. PMID 16704454.
  2. Newton J, Wilkie A, He L, Jordan S, Metallinos D, Holmes N, Jackson I, Barsh G (2000). "Melanocortin 1 receptor variation in the domestic dog". Mamm Genome. 11 (1): 24–30. PMID 10602988.
  3. Schmutz SM, Berryere TG. (June 2007). "The Genetics of Cream Coat Color in Dogs". Journal of Heredity. PMID 17485734.
  4. Eizirik E, Yuhki N, Johnson W, Menotti-Raymond M, Hannah S, O'Brien S (2003). "Molecular genetics and evolution of melanism in the cat family". Curr Biol. 13 (5): 448–53. PMID 12620197.
  5. Klungland H, Våge D, 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. PMID 8535072.
  6. 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.
  7. Theron E, Hawkins K, Bermingham E, Ricklefs R, Mundy N (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. PMID 11369199.
  8. Ritland K, Newton C, Marshall H (2001). "Inheritance and population structure of the white-phased "Kermode" black bear". Curr Biol. 11 (18): 1468–72. PMID 11566108.
  9. Nachman M, Hoekstra H, D'Agostino S (2003). "The genetic basis of adaptive melanism in pocket mice". Proc Natl Acad Sci U S A. 100 (9): 5268–73. PMID 12704245.
  10. Fontanesi L, Tazzoli M, Beretti F, Russo V. (October 2006). "Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus)". Animal genetics. PMID 16978179.
  11. Valverde P, Healy E, Jackson I, Rees J, Thody A (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. PMID 7581459.
  12. Harding R, Healy E, Ray A, Ellis N, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson I, Birch-Machin M, Rees J (2000). "Evidence for variable selective pressures at MC1R". Am J Hum Genet. 66 (4): 1351–61. PMID 10733465.
  14. Mogil J, Ritchie J, Smith S, Strasburg K, Kaplan L, Wallace M, Romberg R, Bijl H, Sarton E, Fillingim R, 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. PMID 15994880.

External links

IUPHAR GPCR Database - Melanocortin MC1 receptor

Further reading

  • Roach, Marion. Roots of Desire: The Myth, Meaning and Sexual Power of Red Hair, Bloomsbury USA, 2005. ISBN 1-58234-344-6
  • Rees, Jonathan. The roots of red hair.

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