Biology:Melanocortin 1 receptor

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Short description: Protein controlling mammalian coloration


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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 hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). It is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase[1] in cells expressing this receptor. It is normally expressed in skin and melanocytes, and to a lesser degree in periaqueductal gray matter, astrocytes and leukocytes.[2] In skin cancer, MC1R is highly expressed in melanomas but not carcinomas.[3]

MC1R is one of the key proteins involved in regulating mammalian skin color and hair color. It is located on the plasma membrane of specialized cells known as melanocytes, which produce the pigment melanin through the process of melanogenesis. It controls the type of melanin being produced, and its activation causes the melanocyte to switch from generating the yellow-red phaeomelanin by default to the brown-black eumelanin in replacement.

In humans, a number of loss-of-function mutations of MC1R have been described, with redheads often having multiple individual loss-of-function mutations, but as of 2001, activating mutations that increase eumelanin synthesis have not been described.[4]

MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes, and susceptibility to infections and pain.[5]

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.[6] When activated by one of the variants of MSH, typically α-MSH, MC1R initiates a complex signaling cascade that leads to the production of 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 yellow and black agouti banding pattern observed on most mammalian hair is caused by the pulsative nature of ASIP signalling through MC1R. Exceptions include particoloured bay horses, which have reddish bodies, and black legs, mane, and tail, where ASIP signaling is limited to regions instead of pulsating. Human hair, which is neither banded nor particoloured, is thought to be regulated by α-MSH signaling through MC1R exclusively.

The prevalence of red hair in humans varies considerably worldwide. In the United States, about 25% of the human 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).[7] 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.[8] Eight genes have been identified in humans that control whether the MC1R gene is turned on and the person has red hair.[9]

Coloration in birds

MC1R is responsible for melanic polymorphisms in at least three unrelated species: the bananaquit, the snow goose, and the arctic skua.[10]

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 analgesics.[11] 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.[12]

Humans with MC1R mutations have been reported to need approximately 20% more inhalational anaesthetic than controls.[13] Lidocaine was reported to be much less effective in reducing pain in another study of humans with MC1R mutations[14]

Model of melanocortin receptors and erythropoiesis

Some roles in development

Since G protein–coupled receptors 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).[15] The same report showed that neutralizing antibodies to MC1R prevented phosphorylation of STAT5 by erythropoietin, and that MC2R and MC5R were also involved, as shown in their model.

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.[16] 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.[17] 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.[18] 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.[19][20] There are single nucleotide polymorphisms in MC1R that are associated with predisposition to nonmelanoma skin cancer.[21] 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.[22] A review has discussed the role of some MC1R variants in melanoma and basal and squamous cell carcinomas independent of pigment production.[20]

Role in kidney pathology

Membranous glomerulonephritis is a serious human disease that can be treated with ACTH, which is a known 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,[23][24] which may help explain the benefit of ACTH in humans.

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'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.[25] 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.

Ligands

Agonists

  • α-MSH - nonselective peptide full agonist
  • β-MSH - nonselective peptide full agonist
  • γ-MSH - nonselective peptide full agonist
  • 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

Pigmentation genetics

MC1R gene expression is regulated by the microphthalmia-associated transcription factor (MITF).[26][27] Mutations of the MC1R gene either can 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, whereas alleles for dysfunctional MC1R are recessive and result in a light coat colour.[28] Variants of MC1R associated with black, red/yellow, and white/cream coat colors in numerous animal species have been reported, including:

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.[8]

Asp294His (rs1805009) is a single nucleotide polymorphism (SNP) in the MC1R gene and it is associated with red hair and light skin type.[8][42][22] Other SNPs in the gene, Arg151Cys and Arg160Trp, are also associated with red hair.

The 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 selective pressure on active MC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift.[43] 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.[44] No evidence is known for positive selection of MC1R alleles in Europe[45] and there is no evidence of an association between the emergence of dysfunctional variants of MC1R and the evolution of light skin in European populations. The lightening of skin color in Europeans and East Asians is an example of convergent evolution.[46]

Evolution

Paralogues[47]

See also

References

  1. ↑ "Melanocortin 1 Receptor: Structure, Function, and Regulation". Frontiers in Genetics 7 (95): 95. May 31, 2016. doi:10.3389/fgene.2016.00095. PMID 27303435. 
  2. ↑ "Melanocortin Regulation of Inflammation". Frontiers in Endocrinology 10: 683. 2019. doi:10.3389/fendo.2019.00683. PMID 31649620. 
  3. ↑ "Tissue distribution and differential expression of melanocortin 1 receptor, a malignant melanoma marker". British Journal of Cancer 87 (4): 414–422. August 2002. doi:10.1038/sj.bjc.6600441. PMID 12177778. 
  4. ↑ "The melanocortin 1 receptor (MC1R): more than just red hair". Pigment Cell Research 13 (3): 135–140. June 2000. doi:10.1034/j.1600-0749.2000.130303.x. PMID 10885670. 
  5. ↑ "Red Alert!". 2017-11-02. https://blog.skincancer.org/2017/11/02/red-alert/. 
  6. ↑ Online Mendelian Inheritance in Man (OMIM) 155555
  7. ↑ "The Red Hair Polymorphisms". http://www.myredhairgene.com/page3/page3.html. 
  8. ↑ 8.0 8.1 8.2 "Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans". Nature Genetics 11 (3): 328–330. November 1995. doi:10.1038/ng1195-328. PMID 7581459. 
  9. ↑ "Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability". Nature Communications 9 (1): 5271. December 2018. doi:10.1038/s41467-018-07691-z. PMID 30531825. Bibcode: 2018NatCo...9.5271M. 
  10. ↑ "A window on the genetics of evolution: MC1R and plumage colouration in birds". Proceedings. Biological Sciences 272 (1573): 1633–1640. August 2005. doi:10.1098/rspb.2005.3107. PMID 16087416. 
  11. ↑ "Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans". Journal of Medical Genetics 42 (7): 583–587. July 2005. doi:10.1136/jmg.2004.027698. PMID 15994880. 
  12. ↑ "Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin". PLOS ONE 5 (9): e12498. September 2010. doi:10.1371/journal.pone.0012498. PMID 20856883. Bibcode: 2010PLoSO...512498D. 
  13. ↑ "Anesthetic requirement is increased in redheads". Anesthesiology 101 (2): 279–283. August 2004. doi:10.1097/00000542-200408000-00006. PMID 15277908. 
  14. ↑ "Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads". Anesthesiology 102 (3): 509–514. March 2005. doi:10.1097/00000542-200503000-00006. PMID 15731586. 
  15. ↑ "Melanocortins contribute to sequential differentiation and enucleation of human erythroblasts via melanocortin receptors 1, 2 and 5". PLOS ONE 10 (4): e0123232. 2015. doi:10.1371/journal.pone.0123232. PMID 25860801. Bibcode: 2015PLoSO..1023232S. 
  16. ↑ "Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis". PLOS ONE 9 (9): e105858. 2014. doi:10.1371/journal.pone.0105858. PMID 25191747. Bibcode: 2014PLoSO...9j5858L. 
  17. ↑ "The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization". PLOS ONE 8 (2): e56004. 2013. doi:10.1371/journal.pone.0056004. PMID 23457491. Bibcode: 2013PLoSO...856004J. 
  18. ↑ "Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study". Shock 47 (1): 79–85. January 2017. doi:10.1097/SHK.0000000000000708. PMID 27488084. 
  19. ↑ "Skin phototype: a new perspective". Pigment Cell & Melanoma Research 28 (4): 378–389. July 2015. doi:10.1111/pcmr.12365. PMID 25786343. 
  20. ↑ 20.0 20.1 "Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face". Head & Face Medicine 12: 11. February 2016. doi:10.1186/s13005-016-0106-0. PMID 26850723. 
  21. ↑ "Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review". The British Journal of Dermatology 171 (4): 713–721. October 2014. doi:10.1111/bjd.13283. PMID 25319428. 
  22. ↑ 22.0 22.1 "Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma". The Journal of Investigative Dermatology 116 (2): 224–229. February 2001. doi:10.1046/j.1523-1747.2001.01224.x. PMID 11179997. 
  23. ↑ "Melanocortin 1 receptor agonists reduce proteinuria". Journal of the American Society of Nephrology 21 (8): 1290–1298. August 2010. doi:10.1681/ASN.2009101025. PMID 20507942. 
  24. ↑ "Effects of melanocortin 1 receptor agonists in experimental nephropathies". PLOS ONE 9 (1): e87816. 2014. doi:10.1371/journal.pone.0087816. PMID 24498203. Bibcode: 2014PLoSO...987816L. 
  25. ↑ "Regulation of pigmentation in zebrafish melanophores". Pigment Cell Research 19 (3): 206–213. June 2006. doi:10.1111/j.1600-0749.2006.00307.x. PMID 16704454. 
  26. ↑ "Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R)". Life Sciences 71 (18): 2171–2179. September 2002. doi:10.1016/S0024-3205(02)01996-3. PMID 12204775. 
  27. ↑ "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research 21 (6): 665–676. December 2008. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 
  28. ↑ 28.0 28.1 "Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus)". Animal Genetics 37 (5): 489–493. October 2006. doi:10.1111/j.1365-2052.2006.01494.x. PMID 16978179. 
  29. ↑ "Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function". Cell 72 (6): 827–834. March 1993. doi:10.1016/0092-8674(93)90572-8. PMID 8458079. 
  30. ↑ "Melanocortin 1 receptor variation in the domestic dog". Mammalian Genome 11 (1): 24–30. January 2000. doi:10.1007/s003350010005. PMID 10602988. 
  31. ↑ "The genetics of cream coat color in dogs". The Journal of Heredity 98 (5): 544–548. 2007. doi:10.1093/jhered/esm018. PMID 17485734. 
  32. ↑ "Molecular genetics and evolution of melanism in the cat family". Current Biology 13 (5): 448–453. March 2003. doi:10.1016/S0960-9822(03)00128-3. PMID 12620197. 
  33. ↑ "Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation". Human Molecular Genetics 9 (17): 2531–2537. October 2000. doi:10.1093/hmg/9.17.2531. PMID 11030758. 
  34. ↑ "The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination". Mammalian Genome 6 (9): 636–639. September 1995. doi:10.1007/BF00352371. PMID 8535072. 
  35. ↑ "A possible involvement of melanocortin 1-receptor in regulating feather color pigmentation in the chicken". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1308 (2): 164–168. August 1996. doi:10.1016/0167-4781(96)00100-5. PMID 8764834. 
  36. ↑ "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". Current Biology 11 (8): 550–557. April 2001. doi:10.1016/S0960-9822(01)00158-0. PMID 11369199. 
  37. ↑ "Genetics of plumage color in the Gyrfalcon (Falco rusticolus): analysis of the melanocortin-1 receptor gene". The Journal of Heredity 103 (3): 315–321. 2012. doi:10.1093/jhered/ess023. PMID 22504110. 
  38. ↑ "Inheritance and population structure of the white-phased "Kermode" black bear". Current Biology 11 (18): 1468–1472. September 2001. doi:10.1016/S0960-9822(01)00448-1. PMID 11566108. 
  39. ↑ "The genetic basis of adaptive melanism in pocket mice". Proceedings of the National Academy of Sciences of the United States of America 100 (9): 5268–5273. April 2003. doi:10.1073/pnas.0431157100. PMID 12704245. Bibcode: 2003PNAS..100.5268N. 
  40. ↑ "Born blonde: a recessive loss-of-function mutation in the melanocortin 1 receptor is associated with cream coat coloration in Antarctic fur seals". Ecology and Evolution 6 (16): 5705–5717. August 2016. doi:10.1002/ece3.2290. PMID 27547348. 
  41. ↑ "Nuclear gene indicates coat-color polymorphism in mammoths". Science 313 (5783): 62. July 2006. doi:10.1126/science.1128994. PMID 16825562. http://oceanrep.geomar.de/28050/1/2006_Roempler-etal-Gne_Science-313-5783.pdf. 
  42. ↑ "Melanocortin 1 receptor variants in an Irish population". The Journal of Investigative Dermatology 111 (1): 119–122. July 1998. doi:10.1046/j.1523-1747.1998.00252.x. PMID 9665397. 
  43. ↑ "Colloquium paper: human skin pigmentation as an adaptation to UV radiation". Proceedings of the National Academy of Sciences of the United States of America 107 (Suppl 2): 8962–8968. May 2010. doi:10.1073/pnas.0914628107. PMID 20445093. Bibcode: 2010PNAS..107.8962J. 
  44. ↑ "Melanocortin-1 receptor gene variants in four Chinese ethnic populations". Cell Research 11 (1): 81–84. March 2001. doi:10.1038/sj.cr.7290070. PMID 11305330. 
  45. ↑ "Evidence for variable selective pressures at MC1R". American Journal of Human Genetics 66 (4): 1351–1361. April 2000. doi:10.1086/302863. PMID 10733465. 
  46. ↑ "Genetic evidence for the convergent evolution of light skin in Europeans and East Asians". Molecular Biology and Evolution 24 (3): 710–722. March 2007. doi:10.1093/molbev/msl203. PMID 17182896. 
  47. ↑ "GeneCards®: The Human Gene Database". https://www.genecards.org/cgi-bin/carddisp.pl?gene=MC1R&keywords=mc1r#paralogs. 

Further reading

External links



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