Melanocortin 1 receptor

The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide 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 the process of 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.

Function

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.^[5] When activated by one of the variants of MSH, typically α-MSH, MC1R initiates a complex signaling cascade that leads to the production of the brown or black pigment eumelanin. In contrast, the receptor can also be antagonized by agouti signalling peptide (ASIP), which reverts the cell back to producing the yellow or red phaeomelanin.

The pulsatile nature of ASIP signalling through MC1R produces the characteristic yellow and black agouti banding pattern observed on most mammalian hair. In some species, ASIP signaling is not of a pulsative nature, but is limited to certain regions. This is especially conspicuous in horses, where a bay horse has black legs, mane, and tail, but a reddish body. A notable exception to this is human hair, which is neither banded nor particoloured, so is thought to be regulated by α-MSH signaling through MC1R exclusively.

In the United States, about 25% of the population carries the mutated melanocortin 1 receptor that causes red hair. With one in four people as carriers, the chance of two people having a child with red hair is about 2% (one in 64).^[6] The prevalence of red hair varies considerably worldwide.

In mutant yellow-orange mice and human redheads, both with nonfunctional MC1R, both genotypes display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to morphine-metabolite analgesics.^[7] 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% 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.^[8]

Ligands

Agonists

• α-MSH - nonselective peptide full agonist
• β-MSH - nonselective peptide full agonist
• γ-MSH - nonselective peptide full agonist
• ACTH - nonselective peptide full agonist
• Afamelanotide - nonselective peptide full agonist
• BMS-470,539 - selective small-molecule full agonist
• Bremelanotide - nonselective peptide full agonist
• Melanotan II - nonselective peptide full agonist
• Modimelanotide - nonselective peptide full agonist
• Setmelanotide - nonselective peptide full agonist

Antagonists

• Agouti signalling peptide - nonselective peptide antagonist

In other organisms

Zebrafish MC1R mediates the response of fish chromatophores on exposure to dark (top), in comparison to light (bottom), environments.

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.^[9] 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.

Pigmentation genetics

MC1R gene expression is regulated by the microphthalmia-associated transcription factor (MITF).^[10][11] 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:

• Laboratory mice^[12]
• Dogs^[13][14]
• Big cats^[15]
• Horses^[16]
• Cattle^[17]
• Chickens^[18]
• Bananaquit^[19]
• Gyrfalcon^[20]
• Kermode bears^[21]
• Rock pocket mice^[22]
• Domestic rabbits^[23]
• Antarctic fur seals^[24]
• Mammoth^[25]

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.^[8]

The Out-of-Africa model proposes that modern humans originated in Africa and migrated north to populate Europe and Asia. These migrants most likely had a functional MC1R variant and, accordingly, dark hair and skin as displayed by indigenous Africans today. As humans migrated north, the absence of high levels of solar radiation in northern Europe and Asia relaxed the selective pressure on active MC1R, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift.^[26] 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.^[27] No evidence is known for positive selection of MC1R alleles in Europe^[28] and there is no evidence of an association between MC1R and the evolution of light skin in European populations.^[29]

See also

• Chromatophore
• Melanocyte
• SLC24A5
• Melanin
• Pigment
• Human skin color
• Freckles
• Melanotropin receptor

References

Further reading

External links

• "Melanocortin Receptors: MC₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 
• Melanocortin Receptor 1 at the US National Library of Medicine Medical Subject Headings (MeSH)