Coloration in mammals The MC1R protein lies within the
cell membrane, and is signalled by
melanocyte-stimulating hormone (MSH) released by the
pituitary gland. 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). 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.
Coloration in birds MC1R is responsible for melanic polymorphisms in at least three unrelated species: the
bananaquit, the
snow goose, and the arctic skua.
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. 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. Humans with MC1R mutations have been reported to need approximately 20% more
inhalational anaesthetic than controls.
Lidocaine was reported to be much less effective in reducing pain in another study of humans with MC1R mutations
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). 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. 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. 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. 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. 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. A review has discussed the role of some MC1R variants in
melanoma and basal and squamous cell carcinomas independent of pigment production.
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, which may help explain the benefit of ACTH in humans.
In other organisms 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.
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 ==