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Melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
Identifiers
Symbols MC1R; MGC14337; MSH-R
External IDs OMIM155555 MGI99456 HomoloGene1789 IUPHAR: MC1 GeneCards: MC1R Gene
Orthologs
Species Human Mouse
Entrez 4157 17199
Ensembl ENSG00000198211 ENSMUSG00000074037
UniProt Q01726 Q75NA2
RefSeq (mRNA) NM_002386 NM_008559
RefSeq (protein) NP_002377 NP_032585
Location (UCSC) Chr 16:
88.51 - 88.51 Mb
Chr 8:
126.29 - 126.29 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.

Contents

Protein function

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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 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

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.[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

MC1R gene expression is regulated by the Microphthalmia-associated transcription factor[2][3]. 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.[14]

This discovery provoked interest in determining why there is an unusual prevalence of red hair and pale 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 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 prevalence 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.[15]

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.[16]

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.[17]

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

References

  1. ^ 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.  
  2. ^ 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.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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. PMID 12704245.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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. PMID 10733465.  
  16. ^ "Scottish redheads 'more sexually attractive'". Ananova. http://www.ananova.com/news/story/sm_80720.html. Retrieved 2007-10-31.  
  17. ^ 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. PMID 15994880.  

External links

Further reading

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


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