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).

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 the process of
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.

MC1R has also been reported to be involved in cancer (independent of skin

coloration), developmental processes, and susceptibility to infections and pain.[5]

Contents
1 Functions
1.1 Coloration in mammals
1.2 Pain in mammals
1.3 Some roles in development
1.4 MC1R and infection/inflammation
1.5 Role in cancer independent of skin color
1.6 Role in kidney pathology
2 Ligands
2.1 Agonists
2.2 Antagonists
2.3 In other organisms
3 Pigmentation genetics
4 See also
5 References
6 Further reading
7 External links
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 a-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 signalling peptide (ASIP), which
reverts the cell back to producing the yellow or red phaeomelanin.

The pulsatile nature of ASIP signalling 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, so is thought to be regulated by
a-MSH signaling through MC1R exclusively.

In the United States, about 25% of the 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] The prevalence
of red hair varies considerably worldwide. 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]
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.[10] 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.[11]

Humans with MC1R mutations have been reported to need approximately 20% more
Inhalational anaesthetic than controls.[12] Lidocaine was reported to be much less
effective in reducing pain in another study of humans with MC1R mutations[13]

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).[14] 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.[15] 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.[16] 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.[17] 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.[18]
[19] There are single nucleotide polymorphisms in MC1R that are associated with
predisposition to nonmelanoma skin cancer.[20] 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[21] A review
has discussed the role of some MC1R variants in melanoma and basal and squamous
cell carcinomas independent of pigment production.[19]

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,[22][23] which may help explain the benefit of
ACTH in humans.

Ligands
Agonists
a-MSH - nonselective peptide full agonist
�-MSH - nonselective peptide full agonist
?-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
Agouti signalling peptide - nonselective peptide antagonist
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, a-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.[24] 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 (MITF).[25][26] 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.[27] Variants of MC1R associated with black, red/yellow, and
white/cream coat colors in numerous animal species have been reported, including:

Laboratory mice[28]
Dogs[29][30]
Big cats[31]
Horses[32]
Cattle[33]
Chickens[34]
Bananaquit[35]
Gyrfalcon[36]
Kermode bears[37]
Rock pocket mice[38]
Domestic rabbits[27]
Antarctic fur seals[39]
Mammoth[40]