The melanocortin 1 receptor (also known as melanocyte-stimulating hormone receptor or Mc1r) is one of the key proteins in regulating hair and skin color. A member of the G-protein-coupled receptor family of proteins, it functions at the surface of specialist pigment producing cells (called melanocytes) to regulate melanogenesis in mammals.
When stimulated by one of the cleavage products of proopiomelanocortin, typically α-melanocyte stimulating hormone (α-MSH), Mc1r initiates a complex signalling cascade that leads to the production of black or brown eumelanin. In most mammals, this signal can be altered by the binding of another protein to Mc1r. Agouti signalling peptide (Asip), a paracrine signalling factor, anatagonizes α-MSH activation of Mc1r and results in a switch to the production of red or yellow 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 signalling 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 signalling through Mc1r exclusively.
Mc1r has a slightly different function in cold-blooded animals such as fish, amphibians and reptiles. Here α-melanocyte stimulating hormone 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. 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.
Mutations of the Mc1rgene can either 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, 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):
In 1995 a landmark study demonstrated that over 80% of humans with red hair 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 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 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 selection driving these changes. Instead, the absence of high levels of solar radiation in northern Europe relaxed the selective pressure on active Mc1r, allowing the gene to mutate into dysfunctional variants without reproductive penalty, then propagate by genetic drift.
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.
A role outside pigmentation
Recent experiments by researchers at McGill University, Montreal, Canada 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 morphine-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.
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