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
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
which binds to a class of pituitary
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
hormoneA hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms...
s known as the
melanocortinThe melanocortins are a group of peptide hormones which include adrenocorticotropic hormone and the different forms of melanocyte-stimulating hormone . They can be synthetic or endogenously produced from proopiomelanocortin in the pituitary gland. The melanocortins exert their effects by binding...
s, of which include
adrenocorticotropic hormoneAdrenocorticotropic hormone , also known as corticotropin, is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress...
(ACTH) and the different forms of
melanocyte-stimulating hormoneThe melanocyte-stimulating hormones are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland. They were first isolated by the Yale professor Aaron B. Lerner...
(MSH). MC1R is one of the key
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
s involved in regulating mammalian
skinHuman skin color can range from almost black to nearly colorless in different people. Skin color is determined primarily by the amount and type of melanin, the pigment in the skin. Variation in skin color is largely due to genetics...
and hair color.
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
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
which binds to a class of pituitary
peptidePeptides are short polymers formed from the linking, in a defined order, of α-amino acids. The link between one amino acid residue and the next is called an amide bond or a peptide bond....
hormoneA hormone is a chemical released by one or more cells that affects cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. It is essentially a chemical messenger that transports a signal from one cell to another. All multicellular organisms...
s known as the
melanocortinThe melanocortins are a group of peptide hormones which include adrenocorticotropic hormone and the different forms of melanocyte-stimulating hormone . They can be synthetic or endogenously produced from proopiomelanocortin in the pituitary gland. The melanocortins exert their effects by binding...
s, of which include
adrenocorticotropic hormoneAdrenocorticotropic hormone , also known as corticotropin, is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress...
(ACTH) and the different forms of
melanocyte-stimulating hormoneThe melanocyte-stimulating hormones are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland. They were first isolated by the Yale professor Aaron B. Lerner...
(MSH). MC1R is one of the key
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
s involved in regulating mammalian
skinHuman skin color can range from almost black to nearly colorless in different people. Skin color is determined primarily by the amount and type of melanin, the pigment in the skin. Variation in skin color is largely due to genetics...
and hair color. It is located on the
plasma membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
of specialized
cell-Science and technology:*Cell , the basic organizational unit of all living organisms*Cell , a term used in electronic circuit design schematics*Cell , a three-dimensional element, part of a higher-dimensional object...
s known as
melanocyteMelanocytes are cells located in the bottom layer of the skin's epidermis, the middle layer of the eye , the inner ear, meninges, bones and heart that produce melanin which is a pigment.-Melanogenesis:...
s, which produce the
pigmentBiological pigments, also known simply as pigments or biochromes are substances produced by living organisms that have a color resulting from selective color absorption. Biological pigments include plant pigments and flower pigments...
melaninMelanin is a class of compounds found in plants, animals, and protists, where it serves predominantly as a pigment. The class of pigments are derivatives of the amino acid tyrosine. Many melanins are insoluble salts and show affinity to water...
through a process referred to as 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 in mammals
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 signaling peptide (ASIP), which reverts the cell back to producing the yellow or red phaeomelanin.
The pulsatile nature of ASIP signaling 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, and thus is thought to be regulated by α-MSH signaling through MC1R exclusively.
MC1R in other organisms
MC1R has a slightly different function in
cold-bloodedA poikilotherm is an animal whose internal temperature varies along with that of the ambient environmental temperature. Most, but not all, ectotherms are poikilothermic...
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 binding to MC1R in regulating this adaptation is unclear, however in teleost fish at least, functional antagonism is provided by
melanin concentrating hormoneMelanin-concentrating hormone is a cyclic 19-amino acid orexinogenic 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 towards a small area in the centre of the melanophore, resulting in the animal having a lighter overall appearance.
Cephalopod{Taxobox| name = Cephalopods| fossil_range = | image = Tafel 054 300.jpg| image_caption = A variety of cephalopod forms from Ernst Haeckel's 1904 Kunstformen der Natur| regnum = Animalia| image_width = 220px| phylum = Mollusca| classis = Cephalopoda...
s generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented
chromatophoreChromatophores are pigment-containing and light-reflecting cells found in amphibians, fish, reptiles, crustaceans, and cephalopods. They are largely responsible for generating skin and eye colour in cold-blooded animals and are generated in the neural crest during embryonic development...
s. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these
invertebrateAn invertebrate is an animal without a vertebral column. The group includes 95% of all animal species — all animals except those in the Chordate subphylum Vertebrata ....
s.
Pigmentation genetics
MC1R geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
expression is regulated by the
Microphthalmia-associated transcription factorMicrophthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
.
MutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
s of the
MC1R gene can either create a
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
that constantly signals, even when not stimulated, or can lower the receptor's activity.
AlleleAn allele is one of a series of different forms of a gene. The word is a short form of allelomorph , which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes...
s for constitutively active
MC1R are inherited dominantly and result in a black coat colour, while alleles for dysfunctional
MC1R are recessive and result in a light coat colour. Variants of
MC1R associated with black, red/yellow and white/cream coat colors in numerous animal
speciesIn biology, a species is:* a taxonomic rank or* a unit at that rank ....
have been reported, including (but not limited to):
- laboratory mice
- dog
The dog is a domesticated form of the Gray Wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The domestic dog has been one of the most widely kept working and companion animals in human history...
s
- big cat
The term big cat - which is not a biological classification - is used informally to distinguish the larger cat species from smaller ones. One definition of "big cat" includes the four members of the genus Panthera: the tiger, lion, jaguar, and leopard. Members of this genus are the only cats able...
s
- cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
- chicken
The chicken is a domesticated fowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other bird...
s
- bananaquit
The Bananaquit, Coereba flaveola, is a passerine bird first described by Linnaeus in his Systema naturae in 1758 as Certhia flaveola.It was reclassified as the only member of the genus Coereba by Louis Jean Pierre Vieillot in 1809....
- Kermode bear
The Kermode Bear , also known as the "spirit bear", is a subspecies of the American Black Bear living in the central coast of British Columbia, and noted for about 1/10 of their population having white or cream-colored coats...
s
- Rock pocket mice
The rock pocket mouse, C. intermedius, is one of 19 species of pocket mice in the genus Chaetodipus....
- Domestic rabbit
A domestic rabbit is any of the several varieties of European rabbit that has been domesticated.Male rabbits are called bucks; females are called does. An older term for an adult rabbit is coney , while rabbit referred only to the young animals...
s
In 1995 a landmark study demonstrated that over 80% of humans with
red hairRed hair varies from a deep orange-red through burnt orange to bright copper. It is characterized by high levels of the reddish pigment pheomelanin and relatively low levels of the dark pigment eumelanin. People with red hair are often referred to as redheads.Approximately 1% to 2% of the human...
or fair skin have a dysfunctional variant of the
MC1R gene.
This discovery provoked interest in determining why there is an unusual prevalence of red hair and pale skin in some northern European populations, specifically
BritainGreat Britain is an island lying to the northwest of Continental Europe. It is the ninth largest island in the world, and the largest European island. With a population of about 59.6 million people, it is the third most populated island on Earth. Great Britain is surrounded by over 1000 smaller...
and
IrelandIreland is the third-largest island in Europe and the twentieth-largest island in the world. It lies to the north-west of continental Europe and is surrounded by hundreds of islands and islets. To the east of Ireland, separated by the Irish Sea, is the island of Great Britain...
. The Out-of-Africa model proposes that modern humans originated in Africa and migrated north to populate Europe and Asia. It is most likely that these migrants had an active
MC1R variant and, accordingly, darker hair and skin (as displayed by indigenous Africans today). Concordant with the migration north, the selective pressure maintaining dark skin decreased as radiation from the sun became less intense. Thus variations in
MC1R began to appear in the human population, resulting in the paler skin and red hair of some Europeans.
Studies find no evidence for
positive selectionIn population genetics, directional selection occurs when natural selection favors a single phenotype and therefore allele frequency continuously shifts in one direction. Under directional selection, the advantageous allele will increase in frequency independently of its dominance relative to...
driving these changes. Instead, the absence of high levels of solar radiation in northern Europe relaxed the
selective pressureIn the context of evolution, certain traits or alleles of a species may be subject to selection. Under selection, individuals with advantageous or "adaptive" traits tend to be more successful than their peers reproductively—meaning they contribute more offspring to the succeeding generation than...
on active
MC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by
genetic driftGenetic drift or allelic drift is the change in the relative frequency with which a gene variant occurs in a population due to random sampling and chance: the alleles in offspring are a random sample of those in the parents, and chance has a role in determining whether a given individual survives...
.
The reason for the unusually high numbers of dysfunctional
MC1R variants in certain human populations is not yet known, though
sexual selectionSexual selection is the theory proposed by Charles Darwin that states that certain evolutionary traits can be explained by intraspecific competition. Darwin defined sexual selection as the effects of the "struggle between the individuals of one sex, generally the males, for the possession of the...
for red hair has been proposed.
A role outside pigmentation
experiments by researchers at
McGill UniversityMcGill University is a public research university located in Montreal, Quebec, Canada. It bears the name of James McGill, a prominent Montreal merchant from Scotland, whose bequest formed the beginning of the university...
,
MontrealMontreal is the second-largest city in Canada and the largest city in the province of Quebec. Originally called Ville-Marie , the city takes its present name from Mont-Royal, the triple-peaked hill located in the heart of the city, whose name was also initially given to the island on which the...
,
CanadaCanada is a country occupying most of northern North America, extending from the Atlantic Ocean in the east to the Pacific Ocean in the west and northward into the Arctic Ocean...
with mutant yellow-orange mice and human redheads, both with non-functional MC1R, show that both genotypes display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to
morphineMorphine is a highly potent opiate analgesic psychoactive drug, is the principal active ingredient in Papaver somniferum , is considered to be the prototypical opioid. Like other opioids, e.g...
-metabolite analgetics.
This work strongly suggests a role for MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known.
See also
- Chromatophore
Chromatophores are pigment-containing and light-reflecting cells found in amphibians, fish, reptiles, crustaceans, and cephalopods. They are largely responsible for generating skin and eye colour in cold-blooded animals and are generated in the neural crest during embryonic development...
- Melanocyte
Melanocytes are cells located in the bottom layer of the skin's epidermis, the middle layer of the eye , the inner ear, meninges, bones and heart that produce melanin which is a pigment.-Melanogenesis:...
- SLC24A5
SLC24A5 is a gene that is thought to explain between 25 and 38% of skin pigmentation variation between Black African and White European humans.Research led by cancer geneticist Keith Cheng and anthropologist Mark D...
- Melanin
Melanin is a class of compounds found in plants, animals, and protists, where it serves predominantly as a pigment. The class of pigments are derivatives of the amino acid tyrosine. Many melanins are insoluble salts and show affinity to water...
- Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
- Human skin color
Human skin color can range from almost black to nearly colorless in different people. Skin color is determined primarily by the amount and type of melanin, the pigment in the skin. Variation in skin color is largely due to genetics...
- Freckles
Further reading
Millington GWM. (2006) Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 31: 407-412.