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.[8]
MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes, and susceptibility to infections and pain.[9]
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.[10] 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).[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]
Coloration in birds
MC1R is responsible for melanic polymorphisms in at least three unrelated species: the
bananaquit, the
snow goose, and the arctic skua.[14]
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.[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 to
capsaicin acting through the
TRPV1 receptor and decreased response to chemically induced inflammatory pain.[16]
Humans with MC1R mutations have been reported to need approximately 20% more
inhalational anaesthetic than controls.[17]Lidocaine was reported to be much less effective in reducing pain in another study of humans with MC1R mutations[18]
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).[19] 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.
One example at the tissue level showed the involvement of MC1R in the normal and pathological development of
articular cartilage in the mouse
knee.[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.
MC1R and infection/inflammation
The involvement of MC1R in a rat model of
Candida albicansvaginitis was investigated.[21] 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.[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 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,[27][28] which may help explain the benefit of ACTH in humans.
In other organisms
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.[29]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.
MC1Rgene expression is regulated by the
microphthalmia-associated transcription factor (MITF).[30][31]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.[32] 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.[12]
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.[47] 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.[48] No evidence is known for
positive selection of MC1R alleles in Europe[49] 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.[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.
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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.
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^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.
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"Melanocortin Receptors: MC1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from
the original on 2021-01-28. Retrieved 2007-07-23.