Melanocortin 1 receptor
Encyclopedia
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
which binds to a class of pituitary peptide
hormone
s known as the melanocortin
s, of which include adrenocorticotropic hormone
(ACTH) and the different forms of melanocyte-stimulating hormone
(MSH). MC1R is one of the key protein
s involved in regulating mammalian skin
and hair color. It is located on the plasma membrane
of specialized cell
s known as melanocyte
s, which produce the pigment
melanin
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.
, 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 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.
In 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 morphine
-metabolite analgetics. These observations suggests a role for mammalian MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known. People with freckles and no red hair, have an 85 percent chance of carrying the defective MC1R gene that is connected to red hair, and the red hair gene. People with no freckles and no red hair have an 18 percent chance of carrying the defective MC1R gene linked to red hair.
MC1R has a slightly different function in cold-blooded
animals such as fish, amphibians and reptiles. Here α-MSH activation of MC1R results in the dispersion of eumelanin filled melanosomes throughout the interior of pigment cells (called melanophores). This gives the skin of the animal a darker hue and often occurs in response to changes in mood or environment. Such a physiological color change implicates MC1R as a key mediator of adaptive cryptic coloration. The role of ASIP 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 towards a small area in the centre of the melanophore, resulting in the animal having a lighter overall appearance. Cephalopod
s generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented chromatophore
s. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these invertebrate
s.
expression is regulated by the microphthalmia-associated transcription factor
(MITF). Mutation
s of the MC1R gene can either create a receptor
that constantly signals, even when not stimulated, or can lower the receptor's activity. Allele
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 species
have been reported, including (but not limited to):
A study on unrelated British and Irish individuals demonstrated that over 80% of people with red hair
and/or fair skin that tans poorly have a dysfunctional variant of the MC1R gene. This is compared to less than 20% in brown or black haired people, and less than 4% in people showing a good tanning response.
This discovery provoked interest in determining why there is an unusual prevalence of red hair and non-tanning skin in some northern European populations, specifically Britain
and Ireland
. 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 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 allelle has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations. of MC1R allelles in Europe and no evidence of an association between MC1R and the evolution of light skin in European populations.
The reason for the unusually high numbers of dysfunctional MC1R variants in certain human populations is not yet known, though sexual selection
for red hair has been proposed.
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
which binds to a class of pituitary peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s known as the melanocortin
Melanocortin
The melanocortins are a group of peptide hormones which include adrenocorticotropic hormone and the different forms of melanocyte-stimulating hormone . They can be synthetic . In humans they can be endogenously produced from proopiomelanocortin in the pituitary gland...
s, of which include adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', 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...
(ACTH) and the different forms of melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(MSH). MC1R is one of the key protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s involved in regulating mammalian skin
Human skin color
Human skin color is primarily due to the presence of melanin in the skin. Skin color ranges from almost black to white with a pinkish tinge due to blood vessels underneath. Variation in natural skin color is mainly due to genetics, although the evolutionary causes are not completely certain...
and hair color. It is located on the plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
of specialized cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s known as melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s, which produce the pigment
Biological pigment
Biological 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...
melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
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.
In mammals
The MC1R protein lies within the cell membraneCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, and is signalled by melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(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 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.
In 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 morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
-metabolite analgetics. These observations suggests a role for mammalian MC1R outside the pigment cell, though the exact mechanism through which the protein can modulate pain sensation is not known. People with freckles and no red hair, have an 85 percent chance of carrying the defective MC1R gene that is connected to red hair, and the red hair gene. People with no freckles and no red hair have an 18 percent chance of carrying the defective MC1R gene linked to red hair.
Agonists
- α-MSHAlpha-Melanocyte-stimulating hormonealpha-Melanocyte-stimulating hormone , also known as alpha-melanotropin, alpha-melanocortin, or alpha-intermedin, is a naturally-occurring endogenous peptide hormone of the melanocortin family, with a tridecapeptide structure and the amino acid sequence...
- non-selective peptide full agonist - AfamelanotideAfamelanotideAfamelanotide developed at the University of Arizona is a synthetic analog of the naturally-occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that has been shown to induce skin pigmentation through melanogenesis and thereby subsequently reduce sun damage to UV exposed...
- selective peptide full agonist - BMS-470,539BMS-470,539BMS-470,539 is a synthetic, small molecule 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 has since been used in scientific research to determine...
- selective small molecule full agonist - BremelanotideBremelanotideBremelanotide is a compound under drug development by Palatin Technologies as a treatment for hemorrhagic shock and reperfusion injury...
- non-selective peptide full agonist - Melanotan IIMelanotan IIMelanotan II developed at the University of Arizona is a synthetic analog of the naturally occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that in usage has been shown to have melanogenesis and aphrodisiac effects in preliminary studies and clinical trials...
- non-selective peptide full agonist
In other organisms
Poikilotherm
A poikilotherm is an organism whose internal temperature varies considerably. It is the opposite of a homeotherm, an organism which maintains thermal homeostasis. Usually the variation is a consequence of variation in the ambient environmental temperature...
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 hormone
Melanin concentrating hormone
Melanin-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
Cephalopod
A cephalopod is any member of the molluscan class Cephalopoda . These exclusively marine animals are characterized by bilateral body symmetry, a prominent head, and a set of arms or tentacles modified from the primitive molluscan foot...
s generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented chromatophore
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...
s. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these invertebrate
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
s.
Pigmentation genetics
MC1R geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
expression is regulated by the microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
(MITF). Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s of the MC1R gene can either create a receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that constantly signals, even when not stimulated, or can lower the receptor's activity. Allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
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 species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
have been reported, including (but not limited to):
- laboratory mice
- dogDogThe domestic 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 dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
s - big catBig catThe term big cat – which is not a biological classification – is used informally to distinguish the larger felid 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 - cattleCattleCattle 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...
- chickenChickenThe chicken is a domesticated fowl, a subspecies of the Red Junglefowl. 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 species of bird...
s - bananaquitBananaquitThe Bananaquit is a species of passerine bird of uncertain relation. It is tentatively placed in the tanager family, but classified as incertae sedis by other authorities such as the American Ornithologists' Union. Its classification is debated, and it is often placed in its own family: Coerebidae...
- Kermode bearKermode bearThe Kermode bear , also known as a "spirit bear" , is a subspecies of the American Black Bear living in the central and north coast of British Columbia, Canada. It is noted for about 1/10 of their population having white or cream-coloured coats...
s - Rock pocket miceRock pocket mouseThe rock pocket mouse, C. intermedius, is one of 19 species of pocket mice in the genus Chaetodipus....
- Domestic rabbitDomestic rabbitA domestic rabbit, or more commonly known as simply the rabbit, is any of the several varieties of European rabbit that have been domesticated....
s
A study on unrelated British and Irish individuals demonstrated that over 80% of people with red hair
Red hair
Red hair occurs on approximately 1–2% of the human population. It occurs more frequently in people of northern or western European ancestry, and less frequently in other populations...
and/or fair skin that tans poorly have a dysfunctional variant of the MC1R gene. This is compared to less than 20% in brown or black haired people, and less than 4% in people showing a good tanning response.
This discovery provoked interest in determining why there is an unusual prevalence of red hair and non-tanning skin in some northern European populations, specifically Britain
Great Britain
Great Britain or Britain is an island situated to the northwest of Continental Europe. It is the ninth largest island in the world, and the largest European island, as well as the largest of the British Isles...
and Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
. 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 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
Selection
In the context of evolution, certain traits or alleles of genes segregating within a population 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...
on active MC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift
Genetic drift
Genetic drift or allelic drift is the change in the frequency of a gene variant in a population due to random sampling.The alleles in the offspring are a sample of those in the parents, and chance has a role in determining whether a given individual survives and reproduces...
. Studies show the MC1R Arg163Gln allelle has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations. of MC1R allelles in Europe and no evidence of an association between MC1R and the evolution of light skin in European populations.
The reason for the unusually high numbers of dysfunctional MC1R variants in certain human populations is not yet known, though sexual selection
Sexual selection
Sexual selection, a concept introduced by Charles Darwin in his 1859 book On the Origin of Species, is a significant element of his theory of natural selection...
for red hair has been proposed.
See also
- ChromatophoreChromatophoreChromatophores 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...
- MelanocyteMelanocyte-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
- SLC24A5SLC24A5Sodium/potassium/calcium exchanger 5 also known as solute carrier family 24 member 5 is a protein that in humans is encoded by the SLC24A5 gene that has a major influence on natural skin colour variation. The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger family...
- MelaninMelaninMelanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
- PigmentPigmentA 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 colorHuman skin colorHuman skin color is primarily due to the presence of melanin in the skin. Skin color ranges from almost black to white with a pinkish tinge due to blood vessels underneath. Variation in natural skin color is mainly due to genetics, although the evolutionary causes are not completely certain...
- Freckles
- Melanotropin receptorMelanotropin receptorMelanotropin receptor is a protein found in skin and eye cells that make melanin . People with certain changes in the gene for the melanotropin receptor have a higher risk of developing melanoma...