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
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
by activating
adenylyl cyclase in cells expressing this receptor. It is normally expressed in skin and
melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
s, and to a lesser degree in
periaqueductal gray matter,
astrocytes and
leukocyte
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s.
In
skin cancer, MC1R is highly expressed in
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
s but not
carcinoma
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...
s.
MC1R is one of the key
proteins involved in regulating
mammalian skin color and
hair color. It is located on the
plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
of specialized
cells
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
known as
melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
s, which produce the
pigment melanin through the process of
melanogenesis
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
. 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
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amin ...
in replacement.
MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes, and susceptibility to infections and pain.
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.
When activated by one of the variants of MSH, typically α-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 α-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). The prevalence of
red hair
Red hair (also known as orange hair and ginger hair) is a hair color found in one to two percent of the human population, appearing with greater frequency (two to six percent) among people of Northern or Northwestern European ancestry and ...
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.
Eight genes have been identified in humans that control whether the MC1R gene is turned on and the person has red hair.
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
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
s.
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
An inhalational anesthetic is a chemical compound possessing general anesthetic properties that can be delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vapori ...
than controls.
Lidocaine
Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...
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
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
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
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
to MC1R prevented phosphorylation of
STAT5
Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the prote ...
by
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
, 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 humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...
. 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
A hospital-acquired infection, also known as a nosocomial infection (from the Greek , meaning "hospital"), is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is ...
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
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
and
DNA repair pathways, as reviewed.
There are
single nucleotide polymorphisms
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
in MC1R that are associated with predisposition to nonmelanoma skin cancer. 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
Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
A review has discussed the role of some MC1R variants in
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
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
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of MC1R improved aspects of kidney morphology and reduced
proteinuria,
which may help explain the benefit of ACTH in humans.
Ligands
Agonists
*
α-MSH
α-Melanocyte-stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family, with a tridecapeptide structure and the amino acid sequence Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. I ...
- 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
BMS-470539 is a small-molecule experimental drug which acts as a potent and highly selective full agonist of the MC1 receptor. It was discovered in 2003 as part of an effort to understand the role of the MC1 receptor in immunomodulation, and ...
- selective small-molecule full agonist
*
Bremelanotide
Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or ...
- nonselective peptide full agonist
*
Melanotan II
Melanotan II is a synthetic analogue of the peptide hormone α-melanocyte-stimulating hormone (α-MSH) that stimulates melanogenesis and increases sexual arousal.
It was under development as drug candidate for female sexual dysfunction and ...
- nonselective peptide full agonist
*
Modimelanotide
Modimelanotide (INN) (code names AP-214, ABT-719, ZP-1480) is a melanocortinergic peptide drug derived from α-melanocyte-stimulating hormone (α-MSH) which was under development by, at different times, Action Pharma, Abbott Laboratories, AbbVi ...
- nonselective peptide full agonist
*
Setmelanotide
Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.
The most common side effects include injection site reactions, skin hyperpigmentation (skin patc ...
- nonselective peptide full agonist
Antagonists
*
Agouti signalling peptide - nonselective peptide antagonist
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
A melanosome is an organelle found in animal cells and is the site for synthesis, storage and transport of melanin, the most common light-absorbing pigment found in the animal kingdom. Melanosomes are responsible for color and photoprotection i ...
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
Camouflage is the use of any combination of materials, coloration, or illumination for concealment, either by making animals or objects hard to see, or by disguising them as something else. Examples include the leopard's spotted coat, the b ...
. 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
Melanin-concentrating hormone (MCH), also known as pro-melanin stimulating hormone (PMCH), is a cyclic 19-amino acid orexigenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish, where it controls skin pigmentation ...
. 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.
Cephalopod
A cephalopod is any member of the molluscan class Cephalopoda (Greek plural , ; "head-feet") such as a squid, octopus, cuttlefish, or nautilus. These exclusively marine animals are characterized by bilateral body symmetry, a prominent head ...
s 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
Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene.
MITF is a basic helix-loop-helix leucine zipper transcription factor ...
(MITF).
Mutations of the ''MC1R'' gene either can create a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
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
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
and result in a light coat colour.
Variants of ''MC1R'' associated with black, red/yellow, and white/cream coat colors in numerous animal
species have been reported, including:
*
Laboratory mice
*
Dogs
*
Big cats
*
Horses
The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million yea ...
*
Cattle
*
Chickens
*
Bananaquit
The bananaquit (''Coereba flaveola'') is a species of passerine bird in the tanager family Thraupidae. Before the development of molecular genetics in the 21st century, its relationship to other species was uncertain and it was either placed with ...
*
Gyrfalcon
*
Kermode bears
*
Rock pocket mice
*
Domestic rabbit
A domestic or domesticated rabbit (''Oryctolagus cuniculus domesticus'')—more commonly known as a pet rabbit, bunny, bun, or bunny rabbit—is a subspecies of European rabbit, a member of the lagomorph family. A male rabbit is known as a ''bu ...
s
*
Antarctic fur seals
*
Mammoth
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.
Asp294His (rs1805009) is a
single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNP) in the ''
MC1R
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 ...
''
gene and it is associated with
red hair
Red hair (also known as orange hair and ginger hair) is a hair color found in one to two percent of the human population, appearing with greater frequency (two to six percent) among people of Northern or Northwestern European ancestry and ...
and light skin type.
Other SNPs in the gene,
Arg151Cys and
Arg160Trp, are also associated with red hair.
The
Out-of-Africa
In paleoanthropology, the recent African origin of modern humans, also called the "Out of Africa" theory (OOA), recent single-origin hypothesis (RSOH), replacement hypothesis, or recent African origin model (RAO), is the dominant model of the ...
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. 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. No evidence is known for
positive selection
In population genetics, directional selection, is a mode of negative natural selection in which an extreme phenotype is favored over other phenotypes, causing the allele frequency to shift over time in the direction of that phenotype. Under dir ...
of ''MC1R'' alleles in Europe
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.
See also
*
Chromatophore
*
Melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
*
SLC24A5
*
Melanin
*
Pigment
*
Human skin color
*
Freckles
Freckles are clusters of concentrated melaninized cells which are most easily visible on people with a fair complexion. Freckles do not have an increased number of the melanin-producing cells, or melanocytes, but instead have melanocytes that ...
*
Melanotropin receptor
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 hormon ...
References
Further reading
*
*
*
*
*
External links
*
*
{{DEFAULTSORT:Melanocortin 1 Receptor
G protein-coupled receptors
Human proteins
Hair color
Skin pigmentation
Mutated genes
Genes on human chromosome 16