Melanocortin 1 receptor
|Symbols||; CMM5; MSH-R; SHEP2|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor that binds to a class of pituitary peptide hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). MC1R is one of the key proteins involved in regulating mammalian skin and hair color. It is located on the plasma membrane of specialized cells known as melanocytes, which produce the pigment melanin through 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 and humans
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, and thus is thought to be regulated by α-MSH signaling through MC1R exclusively.
In the United States, approximately 25% of the population are carrying the mutated Melanocortin 1 Receptor that causes red hair. With 1 in 4 people as carriers, the chance of two people having a child with red hair is about 2% (1 in 64). The prevalence of red hair varies considerably worldwide.
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 analgesics. 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. People with freckles and no red hair have an 85 percent chance of carrying the defective MC1R gene that is connected to red hair. People with no freckles and no red hair have an 18 percent chance of carrying the defective MC1R gene linked to red hair.
- α-MSH - non-selective peptide full agonist
- β-MSH - non-selective peptide full agonist
- γ-MSH - non-selective peptide full agonist
- ACTH - non-selective peptide full agonist
- Afamelanotide - non selective peptide full agonist
- BMS-470,539 - selective small-molecule full agonist
- Bremelanotide - non-selective peptide full agonist
- Melanotan II - non-selective peptide full agonist
- Modimelanotide - non-selective peptide full agonist
- Setmelanotide - non-selective peptide full agonist
- Agouti signalling peptide - non-selective 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 throughout the interior of pigment cells (called melanophores). This gives the skin of the animal a darker hue and often occurs in response to changes in mood or environment. Such a physiological color change implicates MC1R as a key mediator of adaptive cryptic coloration. The role of ASIP's binding to MC1R in regulating this adaptation is unclear; however, in teleost fish at least, functional antagonism is provided by melanin-concentrating hormone. This signals through its receptor to aggregate the melanosomes toward a small area in the centre of the melanophore, resulting in the animal's having a lighter overall appearance. Cephalopods generate a similar, albeit more dramatic, pigmentary effect using muscles to rapidly stretch and relax their pigmented chromatophores. MC1R does not appear to play a role in the rapid and spectacular colour changes observed in these invertebrates.
MC1R gene expression is regulated by the microphthalmia-associated transcription factor (MITF). Mutations of the MC1R gene either can create a receptor that constantly signals, even when not stimulated, or can lower the receptor's activity. Alleles for constitutively active MC1R are inherited dominantly and result in a black coat colour, whereas alleles for dysfunctional MC1R are recessive and result in a light coat colour. 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):
- laboratory mice
- big cats
- Kermode bears
- Rock pocket mice
- Domestic rabbits
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.
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 allele has a high frequency in East Asia and may be part of the evolution of light skin in East Asian populations. There is no evidence for positive selection of MC1R alleles in Europe and no evidence of an association between MC1R and the evolution of light skin in European populations.
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