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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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
that binds to a class of
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
peptide hormone Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...
s known as the
melanocortin The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors.Ericson, M.D., et al., ''Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.'' Biochim Biophys Acta Mol B ...
s, which include
adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH) and the different forms of
melanocyte-stimulating hormone The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating ...
(MSH). It is coupled to Gαs and upregulates levels of
cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...
by activating
adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...
in cells expressing this receptor. It is normally expressed in skin and
melanocyte Melanocytes are melanin-producing neural-crest, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the eye (the uvea), the inner ear, vagina ...
s, and to a lesser degree in periaqueductal gray matter,
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s and
leukocyte White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s. In
skin cancer Skin cancers are cancers that arise from the Human skin, skin. They are due to the development of abnormal cells (biology), cells that have the ability to invade or metastasis, spread to other parts of the body. It occurs when skin cells grow ...
, MC1R is highly expressed in
melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
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, mesoder ...
s. MC1R is one of the key
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s involved in regulating
mammalian A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
skin color Human skin color ranges from the darkest brown to the lightest hues. Differences in skin color among individuals is caused by variation in pigmentation, which is largely the result of genetics (inherited from one's biological parents), and in ...
and
hair color Human hair color is the pigmentation of human hair follicles and shafts due to two types of melanin: eumelanin and pheomelanin. Generally, the more melanin present, the darker the hair. Its tone depends on the ratio of black or brown eume ...
. It is located on the
plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
of specialized
cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...
known as
melanocyte Melanocytes are melanin-producing neural-crest, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the eye (the uvea), the inner ear, vagina ...
s, which produce the
pigment A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), chemically unreactive in water or another medium; in contrast, dyes are colored sub ...
melanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...
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 foun ...
. It controls the type of melanin being produced, and its activation causes the melanocyte to switch from generating the yellow-red
phaeomelanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...
by default to the brown-black
eumelanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...
in replacement. In humans, a number of
loss-of-function mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
s 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. 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 The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
, and is signalled by
melanocyte-stimulating hormone The melanocyte-stimulating hormones, known collectively as MSH, also known as melanotropins or intermedins, are a family of peptide hormones and neuropeptides consisting of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating ...
(MSH) released by the
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
gland. When activated by one of the variants of MSH, typically α-MSH, MC1R initiates a complex
signaling cascade A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
that leads to the production of eumelanin. In contrast, the receptor can also be antagonized by
agouti signalling peptide Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment ...
(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 Red hair, also known as ginger hair, is a human hair color found in 2–6% of people of northern Europe, Northern or Northwestern European ancestry and lesser frequency in other populations. It is most common in individuals Zygosity#Homozy ...
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. Eight genes have been identified in humans that control whether the MC1R gene is turned on and the person has red hair.


Coloration in birds

MC1R is responsible for melanic polymorphisms in at least three unrelated species: the
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 ...
, the
snow goose The snow goose (''Anser caerulescens'') is a species of goose native to North America. Both white and dark morphs exist, the latter often known as blue goose. Its name derives from the typically white plumage. The species was previously placed ...
, 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 Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
-metabolite
analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
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 Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) (, rarely ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a potent Irritation, irritant for Mammal, mammals, including humans, and produces ...
acting through the
TRPV1 The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of ...
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 is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser ...
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 and ventricular fibrillation. When used for local anae ...
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 receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
s 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 biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
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 Erythropoiesis (from Greek ''erythro'', meaning ''red'' and ''poiesis'', meaning ''to make'') is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is s ...
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) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
to MC1R prevented phosphorylation of STAT5 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 th ...
, 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 Hyaline cartilage is the glass-like (hyaline) and translucent cartilage found on many joint surfaces. It is also most commonly found in the ribs, nose, larynx, and trachea. Hyaline cartilage is pearl-gray in color, with a firm consistency and has ...
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 ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is usu ...
vaginitis Vaginitis, also known as vulvovaginitis, is inflammation of the vagina and vulva. Symptoms may include itching, burning, pain, discharge, and a bad smell. Certain types of vaginitis may result in complications during pregnancy. The three mai ...
was investigated. These authors suggest that MC1R is important in anti-fungal and anti-inflammatory processes, in part because
siRNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...
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 healthcare facility. To emphasize both hospital and nonhospital settings, it is s ...
are of variable importance. One of the most important is complicated
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
, 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 Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
and
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
pathways, as reviewed. There are
single nucleotide polymorphisms In genetics and bioinformatics, 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 ...
in MC1R that are associated with predisposition to nonmelanoma skin cancer. It has been reported that variants of MC1R, even in
heterozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
and independent of their effects on pigmentation, are risk factors for
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma, or rodent ulcer, is the most common type of skin cancer. It often appears as a painless, raised area of skin, which may be shiny with Telangiectasia, small blood vessels ru ...
and
squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises 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 is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
and basal and squamous cell carcinomas independent of pigment production.


Role in kidney pathology

Membranous glomerulonephritis Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people (i.e., those of European, Middle Eastern, or North African ancestry.). It is the sec ...
is a serious human disease that can be treated with
ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
, 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 (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of MC1R improved aspects of kidney morphology and reduced
proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
, 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 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 ...
throughout the interior of pigment cells (called
melanophore Chromatophores are cells that produce color, of which many types are pigment-containing cells, or groups of cells, found in a wide range of animals including amphibians, fish, reptiles, crustaceans and cephalopods. Mammals and birds, in contrast ...
s). 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. 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 Taxonomic rank, class Cephalopoda (Greek language, Greek plural , ; "head-feet") such as a squid, octopus, cuttlefish, or nautilus. These exclusively marine animals are characterized by bilateral symm ...
s generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented
chromatophore Chromatophores are cells that produce color, of which many types are pigment-containing cells, or groups of cells, found in a wide range of animals including amphibians, fish, reptiles, crustaceans and cephalopod A cephalopod is any member o ...
s. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these
invertebrate Invertebrates are animals that neither develop nor retain a vertebral column (commonly known as a ''spine'' or ''backbone''), which evolved from the notochord. It is a paraphyletic grouping including all animals excluding the chordata, chordate s ...
s.


Ligands


Agonists

* α-MSH - nonselective peptide full agonist * β-MSH - nonselective peptide full agonist * γ-MSH - nonselective peptide full agonist *
ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
- nonselective peptide full agonist *
Afamelanotide Afamelanotide, sold under the brand name Scenesse, is a medication used to prevent phototoxicity and to reduce pain from light exposure for people with erythropoietic protoporphyria. It is a melanocortin 1 receptor (MC1 receptor) agonist an ...
- nonselective peptide full agonist * BMS-470,539 - 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, ...
- 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 to facilitate tanning. It may also increase sexual arousal. It was developed as a successor to ''afamelanotid ...
- nonselective peptide full agonist *
Modimelanotide Modimelanotide (International Nonproprietary Name, 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 P ...
- 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 pat ...
- nonselective peptide full agonist


Antagonists

*
Agouti signalling peptide Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment ...
- nonselective peptide antagonist


Pigmentation genetics

''MC1R''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
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).
Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s of the ''MC1R'' gene either can create a
receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
that constantly signals, even when not stimulated, or can lower the receptor's activity.
Allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s 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 ...
and result in a light coat colour. Variants of ''MC1R'' associated with black, red/yellow, and white/cream coat colors in numerous animal
species A species () is often defined as the largest group of organisms in which any two individuals of the appropriate sexes or mating types can produce fertile offspring, typically by sexual reproduction. It is the basic unit of Taxonomy (biology), ...
have been reported, including: *
Laboratory mice The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory animal sources for these mice are usually of the species ''Mus musculus''. They a ...
*
Dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the gray wolf. Also called the domestic dog, it was selectively bred from a population of wolves during the Late Pleistocene by hunter-gatherers. ...
s *
Big cat The term "big cat" is typically used to refer to any of the five living members of the genus ''Panthera'', namely the tiger, lion, jaguar, leopard, and snow leopard. All cats descend from the ''Felidae'' family, sharing similar musculature, c ...
s *
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 milli ...
*
Cattle Cattle (''Bos taurus'') are large, domesticated, bovid ungulates widely kept as livestock. They are prominent modern members of the subfamily Bovinae and the most widespread species of the genus '' Bos''. Mature female cattle are calle ...
*
Chicken The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...
s *
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 The gyrfalcon ( or ) (), also abbreviated as gyr, is a bird of prey from the genus ''Falco'' (falcons and kestrels) and the largest species of the family Falconidae. A high-latitude species, the gyrfalcon breeds on the Arctic coasts and tundra, ...
*
Kermode bear The spirit bear, sometimes called the Kermode bear (''Ursus americanus kermodei''), is a subspecies of the American black bear and lives in the Central and North Coast regions of British Columbia, Canada. It is the official provincial mammal o ...
s * Rock pocket mice *
Domestic rabbit The domestic rabbit (''Oryctolagus cuniculus domesticus'') is the domestication, domesticated form of the European rabbit, a member of the lagomorph order. A male rabbit is known as a ''buck,'' a female as a ''doe,'' and a young rabbit as a ''k ...
s *
Antarctic fur seal The Antarctic fur seal (''Arctocephalus gazella'') is one of eight seals in the genus '' Arctocephalus'', and one of nine fur seals in the subfamily Arctocephalinae. Despite what its name suggests, the Antarctic fur seal is mostly distributed i ...
s *
Mammoth A mammoth is any species of the extinct elephantid genus ''Mammuthus.'' They lived from the late Miocene epoch (from around 6.2 million years ago) into the Holocene until about 4,000 years ago, with mammoth species at various times inhabi ...
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 and bioinformatics, 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 ...
(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 hormon ...
''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
and it is associated with
red hair Red hair, also known as ginger hair, is a human hair color found in 2–6% of people of northern Europe, Northern or Northwestern European ancestry and lesser frequency in other populations. It is most common in individuals Zygosity#Homozy ...
and light skin type. Other SNPs in the gene, Arg151Cys and Arg160Trp, are also associated with red hair. The
Out-of-Africa The recent African origin of modern humans or the "Out of Africa" theory (OOA) is the most widely accepted paleoanthropology, paleo-anthropological model of the geographic origin and Early human migrations, early migration of early modern h ...
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 Sunlight is the portion of the electromagnetic radiation which is emitted by the Sun (i.e. solar radiation) and received by the Earth, in particular the visible light perceptible to the human eye as well as invisible infrared (typically p ...
in northern Europe and Asia relaxed the
selective pressure Evolutionary pressure, selective pressure or selection pressure is exerted by factors that reduce or increase reproductive success in a portion of a population, driving natural selection. It is a quantitative description of the amount of change oc ...
on active ''MC1R'', allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by
genetic drift Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the Allele frequency, frequency of an existing gene variant (allele) in a population due to random chance. Genetic drift may cause gene va ...
. 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 type of natural selection in which one extreme phenotype is favored over both the other extreme and moderate phenotypes. This genetic selection causes the allele frequency to shift toward the ...
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 Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last comm ...
.


Evolution


Paralogues Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

Source: * MC4R * MC3R *
MC5R Melanocortin 5 receptor (MC5R) is a protein that in humans is encoded by the gene. It is located on the chromosome 18 in the human genome. When the MC5R was disrupted in Genetically modified organism, transgenic mice, it induced disruption of th ...
* MC2R *
GPR6 G protein-coupled receptor 6, also known as GPR6, is a protein which in humans is encoded by the ''GPR6'' gene. Function GPR6 is a member of the G protein-coupled receptor family of transmembrane receptors. It has been reported that GPR6 is b ...
*
GPR12 Probable G-protein coupled receptor 12 is a protein that in humans is encoded by the ''GPR12'' gene. The gene product of GPR12 is an orphan receptor, meaning that its endogenous ligand is currently unknown. Gene disruption of GPR12 in mice resul ...
*
S1PR2 Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Function This protein participates in sphingos ...
*
GPR3 G-protein coupled receptor 3 is a protein that in humans is encoded by the ''GPR3'' gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction. GPR ...
*
S1PR1 Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1PR1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the ''S1PR1'' gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive s ...
*
LPAR1 Lysophosphatidic acid receptor 1 also known as LPA1 is a protein that in humans is encoded by the ''LPAR1'' gene. LPA1 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA). Function The integral ...
*
CNR1 Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. And discovered, by determination and characterization in 1988, and cloned in 1990 for the first time. The human CB1 recepto ...
*
LPAR2 Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the ''LPAR2'' gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA). Function This gene enc ...
*
GPR119 G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the ''GPR119'' gene. GPR119, along with GPR55 and GPR18, have been implicated as novel cannabinoid receptors. Pharmacology GPR ...
*
S1PR3 Sphingosine-1-phosphate receptor 3 also known as ''S1PR3'' is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P3. Function ...
*
S1PR5 Sphingosine-1-phosphate receptor 5 also known as S1PR5 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P5. Agonists * A ...
*
LPAR3 Lysophosphatidic acid receptor 3 also known as LPA3 is a protein in humans that is encoded by the ''LPAR3'' gene. LPA3 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA). Function This gene enc ...
* CNR2 *
S1PR4 Sphingosine-1-phosphate receptor 4 also known as S1PR4 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P4. Function This ...


See also

*
Chromatophore Chromatophores are cells that produce color, of which many types are pigment-containing cells, or groups of cells, found in a wide range of animals including amphibians, fish, reptiles, crustaceans and cephalopod A cephalopod is any member o ...
*
Melanocyte Melanocytes are melanin-producing neural-crest, neural crest-derived cell (biology), cells located in the bottom layer (the stratum basale) of the skin's epidermis (skin), epidermis, the middle layer of the eye (the uvea), the inner ear, vagina ...
* SLC24A5 *
Melanin Melanin (; ) is a family of biomolecules organized as oligomers or polymers, which among other functions provide the pigments of many organisms. Melanin pigments are produced in a specialized group of cells known as melanocytes. There are ...
*
Pigment A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), chemically unreactive in water or another medium; in contrast, dyes are colored sub ...
*
Human skin color Human skin color ranges from the Dark skin, darkest brown to the Light skin, lightest hues. Differences in Human skin, skin color among individuals is caused by variation in pigmentation, which is largely the result of genetics (inherited from o ...
*
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


References


Further reading

* * * * *


External links

* * * {{DEFAULTSORT:Melanocortin 1 Receptor G protein-coupled receptors Human proteins Hair color Human skin color Mutated genes Genes on human chromosome 16