In humans, a number ofloss-of-function mutations of MC1R have been described, withredheads often having multiple individual loss-of-function mutations, but as of 2001, activating mutations that increase eumelanin synthesis have not been described.[8]
MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes, and susceptibility to infections and pain.[9]
The MC1R protein lies within thecell membrane, and is signalled bymelanocyte-stimulating hormone (MSH) released by thepituitary gland.[10] When activated by one of the variants of MSH, typically α-MSH, MC1R initiates a complexsignaling cascade that leads to the production of eumelanin. In contrast, the receptor can also be antagonized byagouti 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 particolouredbay 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 ofred 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).[11] 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.[12] Eight genes have been identified in humans that control whether the MC1R gene is turned on and the person has red hair.[13]
In mutant yellow-orange mice and human redheads, both with nonfunctional MC1R, both genotypes display reduced sensitivity to noxious stimuli and increased analgesic responsiveness tomorphine-metaboliteanalgesics.[15] 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 tocapsaicin acting through theTRPV1 receptor and decreased response to chemically induced inflammatory pain.[16]
Humans with MC1R mutations have been reported to need approximately 20% moreinhalational anaesthetic than controls.[17]Lidocaine was reported to be much less effective in reducing pain in another study of humans with MC1R mutations[18]
Model of melanocortin receptors and erythropoiesis
SinceG protein–coupled receptors are known to activateSignal 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 stoppederythropoiesis from proceeding from the polychromatic cell stage (poly-E in the figure) to the orthochromatic cell stage (ortho-E in the diagram).[19] The same report showed that neutralizingantibodies to MC1R prevented phosphorylation ofSTAT5 byerythropoietin, 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 ofarticular cartilage in the mouseknee.[20] 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.
The involvement of MC1R in a rat model ofCandida albicansvaginitis was investigated.[21] These authors suggest that MC1R is important in anti-fungal and anti-inflammatory processes, in part becausesiRNA knockdown of MC1R almost completely prevented the responses.
Nosocomial infections are of variable importance. One of the most important is complicatedsepsis, 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.[22] Thus, if the association is confirmed, MC1R targeting may become a therapeutic option to prevent severe sepsis.
Membranous glomerulonephritis is a serious human disease that can be treated withACTH, which is a knownagonist of MC1R. In a rat model of nephritis it was found that treatment with a differentagonist of MC1R improved aspects of kidney morphology and reducedproteinuria,[27][28] which may help explain the benefit of ACTH in humans.
Zebrafish MC1R mediates the response of fishchromatophores on exposure to dark (top), in comparison to light (bottom), environments.
MC1R has a slightly different function incold-blooded animals such as fish, amphibians, and reptiles. Here, α-MSH activation of MC1R results in the dispersion of eumelanin-filledmelanosomes throughout the interior of pigment cells (calledmelanophores). 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 adaptivecryptic 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 bymelanin-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.[29]Cephalopods generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmentedchromatophores. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in theseinvertebrates.
MC1Rgene expression is regulated by themicrophthalmia-associated transcription factor (MITF).[30][31]Mutations of theMC1R gene either can create areceptor that constantly signals, even when not stimulated, or can lower the receptor's activity.Alleles for constitutively activeMC1R are inheriteddominantly and result in a black coat colour, whereas alleles for dysfunctionalMC1R arerecessive and result in a light coat colour.[32] Variants ofMC1R associated with black, red/yellow, and white/cream coat colors in numerous animalspecies 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 theMC1R 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.[12]
TheOut-of-Africa model proposes that modern humans originated in Africa and migrated north to populate Europe and Asia. These migrants most likely had a functionalMC1R variant and, accordingly, dark hair and skin as displayed by indigenous Africans today. As humans migrated north, the absence of high levels ofsolar radiation in northern Europe and Asia relaxed theselective pressure on activeMC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate bygenetic drift.[47] Studies show theMC1R Arg163Gln allele has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations.[48] No evidence is known forpositive selection ofMC1R alleles in Europe[49] and there is no evidence of an association between the emergence of dysfunctional variants ofMC1R and the evolution of light skin in European populations. The lightening of skin color in Europeans and East Asians is an example ofconvergent evolution.[50]
^abcValverde P, Healy E, Jackson I, Rees JL, Thody AJ (November 1995). "Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans".Nature Genetics.11 (3):328–330.doi:10.1038/ng1195-328.PMID7581459.S2CID7980311.
^Binstock M, Hafeez F, Metchnikoff C, Arron ST (October 2014). "Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review".The British Journal of Dermatology.171 (4):713–721.doi:10.1111/bjd.13283.PMID25319428.S2CID35603627.
^Aoki H, Moro O (September 2002). "Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R)".Life Sciences.71 (18):2171–2179.doi:10.1016/S0024-3205(02)01996-3.PMID12204775.
^abFontanesi 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.37 (5):489–493.doi:10.1111/j.1365-2052.2006.01494.x.PMID16978179.
^Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, et al. (March 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.PMID8458079.S2CID12179800.
^Newton JM, Wilkie AL, He L, Jordan SA, Metallinos DL, Holmes NG, et al. (January 2000). "Melanocortin 1 receptor variation in the domestic dog".Mammalian Genome.11 (1):24–30.doi:10.1007/s003350010005.PMID10602988.S2CID1755908.
^Klungland H, Våge DI, Gomez-Raya L, Adalsteinsson S, Lien S (September 1995). "The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination".Mammalian Genome.6 (9):636–639.doi:10.1007/BF00352371.PMID8535072.S2CID22044170.
^Takeuchi S, Suzuki H, Yabuuchi M, Takahashi S (August 1996). "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.doi:10.1016/0167-4781(96)00100-5.PMID8764834.
"Melanocortin Receptors: MC1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2021-01-28. Retrieved2007-07-23.
