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). It is coupled to G_αs and upregulates levels of cAMP by activating adenylyl cyclase^[5] in cells expressing this receptor. It is normally expressed in skin and melanocytes, and to a lesser degree in periaqueductal gray matter, astrocytes and leukocytes.^[6] In skin cancer, MC1R is highly expressed in melanomas but not carcinomas.^[7]

MC1R
Identifiers
Aliases	MC1R, CMM5, MSH-R, SHEP2, Melanocortin 1 receptor
External IDs	OMIM: 155555 MGI: 99456 HomoloGene: 1789 GeneCards: MC1R
Gene location (Human) Chr. Chromosome 16 (human)^[1] Band 16q24.3 Start 89,912,119 bp^[1] End 89,920,973 bp^[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)^[2] Band 8 E1|8 72.1 cM Start 124,133,846 bp^[2] End 124,137,483 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube anterior pituitary gastric mucosa left lobe of thyroid gland right lobe of thyroid gland left uterine tube canal of the cervix stromal cell of endometrium minor salivary gland ascending aorta Top expressed in hair follicle iris skin of abdomen yolk sac cornea More reference expression data BioGPS n/a
Gene ontology Molecular function G protein-coupled peptide receptor activity G protein-coupled receptor activity signal transducer activity melanocyte-stimulating hormone receptor activity protein binding melanocortin receptor activity ubiquitin protein ligase binding Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane intracellular anatomical structure Biological process G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger multicellular organism development UV protection negative regulation of tumor necrosis factor production UV-damage excision repair signal transduction positive regulation of protein kinase A signaling intracellular signal transduction pigmentation positive regulation of transcription by RNA polymerase II positive regulation of protein kinase B signaling positive regulation of protein kinase C signaling G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway sensory perception of pain melanin biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4157 17199 Ensembl ENSG00000258839 ENSMUSG00000074037 UniProt Q01726 Q01727 RefSeq (mRNA) NM_002386 NM_008559 RefSeq (protein) NP_002377 NP_032585 Location (UCSC) Chr 16: 89.91 – 89.92 Mb Chr 8: 124.13 – 124.14 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

MC1R is one of the key proteins involved in regulating mammalian skin color 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.

MC1R has also been reported to be involved in cancer (independent of skin coloration), developmental processes, and susceptibility to infections and pain.^[8]

Functions

Coloration in mammals

The MC1R protein lies within the cell membrane, and is signalled by melanocyte-stimulating hormone (MSH) released by the pituitary gland.^[9] 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).^[10] The prevalence of red hair varies considerably worldwide. 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.^[11] Eight genes have been identified in humans that control whether the MC1R gene is turned on and the person has red hair.^[12]

Pain in mammals

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.^[13] 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.

In a certain genetic background in mice it has been reported that animals lacking MC1R had increased tolerance to capsaicin acting through the TRPV1 receptor and decreased response to chemically induced inflammatory pain.^[14]

Humans with MC1R mutations have been reported to need approximately 20% more Inhalational anaesthetic than controls.^[15] Lidocaine was reported to be much less effective in reducing pain in another study of humans with MC1R mutations^[16]

 

Model of melanocortin receptors and erythropoiesis

Some roles in development

Since G protein–coupled receptors are known to activate Signal transduction in cells, it should not be surprising to find MC1R involved in development. As one example at the cellular level, preventing signalling by MC1R stopped erythropoiesis from proceeding from the polychromatic cell stage (poly-E in the figure) to the orthochromatic cell stage (ortho-E in the diagram).^[17] The same report showed that neutralizing antibodies to MC1R prevented phosphorylation of STAT5 by erythropoietin, and that MC2R and MC5R were also involved, as shown in their model.

 

MC1R deficiency and osteoarthritis

One example at the tissue level showed the involvement of MC1R in the normal and pathological development of articular cartilage in the mouse knee.^[18] In this study the authors compared normal mice with mice completely lacking MC1R. Even without experimental induction of osteoarthritis, mice without MC1R had less articular cartilage (as shown by the red staining in the image). After experimental induction of osteoarthritis, the defect caused by MC1R was more pronounced.

MC1R and infection/inflammation

The involvement of MC1R in a rat model of Candida albicans vaginitis was investigated.^[19] These authors suggest that MC1R is important in anti-fungal and anti-inflammatory processes, in part because siRNA knockdown of MC1R almost completely prevented the responses.

Nosocomial infections are of variable importance. One of the most important is complicated sepsis, which was defined as sepsis with organ dysfunction. One variant of MC1R (MC1RR163Q, rs885479) was reported to be associated with lowered risk of developing complicated sepsis during hospitalization after trauma.^[20] Thus, if the association is confirmed, MC1R targeting may become a therapeutic option to prevent severe sepsis.

Role in cancer independent of skin color

MC1R signalling stimulates antioxidant and DNA repair pathways, as reviewed.^[21][22] There are single nucleotide polymorphisms in MC1R that are associated with predisposition to nonmelanoma skin cancer.^[23] It has been reported that variants of MC1R, even in heterozygotes and independent of their effects on pigmentation, are risk factors for basal cell carcinoma and squamous cell carcinoma^[24] A review has discussed the role of some MC1R variants in melanoma and basal and squamous cell carcinomas independent of pigment production.^[22]

Role in kidney pathology

Membranous glomerulonephritis is a serious human disease that can be treated with ACTH, which is a known agonist of MC1R. In a rat model of nephritis it was found that treatment with a different agonist of MC1R improved aspects of kidney morphology and reduced proteinuria,^[25][26] which may help explain the benefit of ACTH in humans.

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.^[27] 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).^[28][29] 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.^[30] Variants of MC1R associated with black, red/yellow, and white/cream coat colors in numerous animal species have been reported, including:

• Laboratory mice^[31]
• Dogs^[32][33]
• Big cats^[34]
• Horses^[35]
• Cattle^[36]
• Chickens^[37]
• Bananaquit^[38]
• Gyrfalcon^[39]
• Kermode bears^[40]
• Rock pocket mice^[41]
• Domestic rabbits^[30]
• Antarctic fur seals^[42]
• Mammoth^[43]

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.^[11]

Asp294His (rs1805009) is a single nucleotide polymorphism (SNP) in the MC1R gene and it is associated with red hair and light skin type.^[11][44][24] Other SNPs in the gene, Arg151Cys and Arg160Trp, are also associated with red hair.

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.^[45] 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.^[46] No evidence is known for positive selection of MC1R alleles in Europe^[47] and there is no evidence of an association between the emergence of dysfunctional variants of MC1R and the evolution of light skin in European populations. The lightening of skin color in Europeans and East Asians is an example of convergent evolution.^[48]

See also

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

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Further reading

• Roach, Marion (2005). Roots of Desire: The Myth, Meaning and Sexual Power of Red Hair. Bloomsbury USA. pp. 256 pages. ISBN 978-1-58234-344-0.
• Rees, Jonathan (2003). . Wellcome Trust. Archived from the original on 2007-10-30. Retrieved 2007-10-31.
• Silvers, Willys K. (1979). The Coat Colors of Mice. Springer-Verlag. ISBN 978-0-387-90367-5.
• Silvers, Willys K. (2003). "The Coat Colors of Mice". Mouse Genome Informatics.
• Millington GW (May 2006). "Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors". Clinical and Experimental Dermatology. 31 (3): 407–12. doi:10.1111/j.1365-2230.2006.02128.x. PMID 16681590. S2CID 25213876.

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)