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Gene Review

MC1R  -  melanocortin 1 receptor (alpha melanocyte...

Homo sapiens

Synonyms: CMM5, MC1-R, MSH-R, MSHR, Melanocortin receptor 1, ...
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Disease relevance of MC1R


Psychiatry related information on MC1R


High impact information on MC1R

  • The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized [12].
  • Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response [13].
  • Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders [14].
  • Despite a large number of murine coat-color mutations, only one gene in humans, the melanocortin 1 receptor (MC1R), is known to account for substantial variation in skin and hair color and in skin cancer incidence [15].
  • It remains to be investigated whether the interaction of MC1R and ASIP can enhance prediction of human pigmentation and melanoma risk [16].

Chemical compound and disease context of MC1R


Biological context of MC1R

  • MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations [1].
  • When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=.01) [1].
  • Mutagenesis studies suggested that the targets of GRK6 are two residues located in the MC1R cytosolic C terminus, Thr-308 and Ser-316 [21].
  • The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer [22].
  • Furthermore, three missense mutations (V92M) and two silent mutations (CGA (Arg) to CGG (Arg), codon 213, exon 6) were found in the MC1R and p53 genes, respectively [23].

Anatomical context of MC1R

  • Herein, we define HLA-A2-restricted CTL epitopes from a recently cloned melanocortin 1 receptor (MC1R), which belongs to a new subfamily of the G-protein-coupled receptors expressed on melanomas and melanocytes [24].
  • Melanocortin receptors (MC1R-MC5R) and their ligands (melanocyte-stimulating hormone (MSH) and adrenocorticotrophin hormone (ACTH)) have been shown to influence physiological functions of cells and organs, including exocrine glands [25].
  • Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling [26].
  • For this purpose, the effect of co-expression of cDNA encoding MITF on MC1R promoter activity in NIH/3T3 cells was studied [27].
  • ACTH and alpha-MSH bind to MC1R to influence both pigmentation and the immune system [28].

Associations of MC1R with chemical compounds

  • However, in the MC1R, these serine residues corresponded to Val(122), which contains two methyl groups that induce steric hindrance with D-Phe(7) of [Gln(6)]alpha-MSH-ND [29].
  • To investigate whether residues in the extracellular domains of melanocortin 1 receptor (MC1R) are required for ligand binding, a number of mutants were constructed where charged residues were converted to alanine [30].
  • These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized [31].
  • Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach [32].
  • The dependence of agonist binding on the dithiothreitol concentration followed a monophasic curve for wild-type hMC4R and its C40A, C271A, and C279A mutants and a biphasic curve for hMC1R, suggesting the presence of at least one structurally and functionally essential disulfide bond in both wild-type receptors and the hMC4R mutants [33].
  • The V92M variant cAMP activation was equal to or higher than that for wild-type MC1R [34].

Physical interactions of MC1R

  • Although previous studies have shown that AGRP binds three of the five known subtypes of melanocortin receptor, the receptor domains participating in binding and the molecular interactions involved are presently unknown [35].
  • We have shown that alpha-MSH and ACTH bind the human MC1R with equal affinity, and are equipotent in their mitogenic and melanogenic effects on human melanocytes [36].
  • Moreover, TRH could be docked into a binding pocket of a molecular model of the MC1 receptor at only a little higher energy than a short cyclic MSH peptide [37].
  • The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes [38].
  • Melanocortin hormones and neurotransmitters regulate a vast array of physiologic processes by interacting with five G-protein-coupled melanocortin receptor types [39].

Regulatory relationships of MC1R


Other interactions of MC1R


Analytical, diagnostic and therapeutic context of MC1R

  • In addition, electrophoretic mobility shift assay indicated that nuclear extracts of human SK-Mel-2 cells contain a protein that binds specifically to the MC1R promoter region containing the CATGTG motif [27].
  • Molecular cloning of a novel human melanocortin receptor [48].
  • Distribution of cDNA for five individual melanocortin receptor subtypes in 20 different human tissues was determined by PCR using subtype specific primers [49].
  • We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups [50].
  • Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors [51].


  1. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Box, N.F., Duffy, D.L., Chen, W., Stark, M., Martin, N.G., Sturm, R.A., Hayward, N.K. Am. J. Hum. Genet. (2001) [Pubmed]
  2. Alpha-melanocyte stimulating hormone potentiates p16/CDKN2A expression in human skin after ultraviolet irradiation. Pavey, S., Gabrielli, B. Cancer Res. (2002) [Pubmed]
  3. Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes. Luscombe, C.J., French, M.E., Liu, S., Saxby, M.F., Jones, P.W., Fryer, A.A., Strange, R.C. Br. J. Cancer (2001) [Pubmed]
  4. MC1R, ASIP, and DNA repair in sporadic and familial melanoma in a Mediterranean population. Landi, M.T., Kanetsky, P.A., Tsang, S., Gold, B., Munroe, D., Rebbeck, T., Swoyer, J., Ter-Minassian, M., Hedayati, M., Grossman, L., Goldstein, A.M., Calista, D., Pfeiffer, R.M. J. Natl. Cancer Inst. (2005) [Pubmed]
  5. Expression and localization of melanocortin-1 receptor in human adipose tissues of severely obese patients. Hoch, M., Eberle, A.N., Wagner, U., Bussmann, C., Peters, T., Peterli, R. Obesity (Silver Spring, Md.) (2007) [Pubmed]
  6. MC1R: three novel variants identified in a malignant melanoma association study in the Spanish population. Fernandez, L., Milne, R., Bravo, J., Lopez, J., Avilés, J., Longo, M., Benítez, J., Lázaro, P., Ribas, G. Carcinogenesis (2007) [Pubmed]
  7. Red hair - a desirable mutation? Ha, T., Rees, J.L. Journal of cosmetic dermatology (2002) [Pubmed]
  8. Plasma agouti-related protein levels in women with anorexia nervosa. Moriya, J., Takimoto, Y., Yoshiuchi, K., Shimosawa, T., Akabayashi, A. Psychoneuroendocrinology (2006) [Pubmed]
  9. The role of the melanocortin system and the melanocortin-4 receptor in ring dove (Streptopelia risoria) feeding behavior. Strader, A.D., Schiöth, H.B., Buntin, J.D. Brain Res. (2003) [Pubmed]
  10. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. Diamond, L.E., Earle, D.C., Heiman, J.R., Rosen, R.C., Perelman, M.A., Harning, R. The journal of sexual medicine. (2006) [Pubmed]
  11. Metabolic activation of a 1,3-disubstituted piperazine derivative: evidence for a novel ring contraction to an imidazoline. Doss, G.A., Miller, R.R., Zhang, Z., Teffera, Y., Nargund, R.P., Palucki, B., Park, M.K., Tang, Y.S., Evans, D.C., Baillie, T.A., Stearns, R.A. Chem. Res. Toxicol. (2005) [Pubmed]
  12. Melanin pigmentation in mammalian skin and its hormonal regulation. Slominski, A., Tobin, D.J., Shibahara, S., Wortsman, J. Physiol. Rev. (2004) [Pubmed]
  13. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Valverde, P., Healy, E., Jackson, I., Rees, J.L., Thody, A.J. Nat. Genet. (1995) [Pubmed]
  14. Targeting melanocortin receptors as a novel strategy to control inflammation. Catania, A., Gatti, S., Colombo, G., Lipton, J.M. Pharmacol. Rev. (2004) [Pubmed]
  15. The genetics of sun sensitivity in humans. Rees, J.L. Am. J. Hum. Genet. (2004) [Pubmed]
  16. A polymorphism in the agouti signaling protein gene is associated with human pigmentation. Kanetsky, P.A., Swoyer, J., Panossian, S., Holmes, R., Guerry, D., Rebbeck, T.R. Am. J. Hum. Genet. (2002) [Pubmed]
  17. Overweight humans are resistant to the weight-reducing effects of melanocortin4-10. Hallschmid, M., Smolnik, R., McGregor, G., Born, J., Fehm, H.L. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  18. Inhibition by melittin and fluphenazine of melanotropin receptor function and adenylate cyclase in M2R melanoma cell membranes. Gerst, J.E., Salomon, Y. Endocrinology (1987) [Pubmed]
  19. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. Wessells, H., Levine, N., Hadley, M.E., Dorr, R., Hruby, V. Int. J. Impot. Res. (2000) [Pubmed]
  20. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response. Diamond, L.E., Earle, D.C., Garcia, W.D., Spana, C. Urology (2005) [Pubmed]
  21. Regulation of human melanocortin 1 receptor signaling and trafficking by thr-308 and ser-316 and its alteration in variant alleles associated with red hair and skin cancer. Sánchez-Laorden, B.L., Jiménez-Cervantes, C., García-Borrón, J.C. J. Biol. Chem. (2007) [Pubmed]
  22. Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation. Scott, M.C., Wakamatsu, K., Ito, S., Kadekaro, A.L., Kobayashi, N., Groden, J., Kavanagh, R., Takakuwa, T., Virador, V., Hearing, V.J., Abdel-Malek, Z.A. J. Cell. Sci. (2002) [Pubmed]
  23. Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi. Papp, T., Pemsel, H., Zimmermann, R., Bastrop, R., Weiss, D.G., Schiffmann, D. J. Med. Genet. (1999) [Pubmed]
  24. Synthetic peptides derived from the melanocyte-stimulating hormone receptor MC1R can stimulate HLA-A2-restricted cytotoxic T lymphocytes that recognize naturally processed peptides on human melanoma cells. Salazar-Onfray, F., Nakazawa, T., Chhajlani, V., Petersson, M., Kärre, K., Masucci, G., Celis, E., Sette, A., Southwood, S., Appella, E., Kiessling, R. Cancer Res. (1997) [Pubmed]
  25. Melanocortin-5 receptor: a marker of human sebocyte differentiation. Zhang, L., Li, W.H., Anthonavage, M., Eisinger, M. Peptides (2006) [Pubmed]
  26. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Solano, F., Briganti, S., Picardo, M., Ghanem, G. Pigment Cell Res. (2006) [Pubmed]
  27. Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R). Aoki, H., Moro, O. Life Sci. (2002) [Pubmed]
  28. Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Millington, G.W. Clin. Exp. Dermatol. (2006) [Pubmed]
  29. Minimization of MC1R selectivity by modification of the core structure of alpha-MSH-ND. Lim, S., Li, S., Lee, C., Yoon, C., Baik, J., Lee, W. Chem. Biol. (2001) [Pubmed]
  30. Identification of ligand binding residues in extracellular loops of the melanocortin 1 receptor. Chhajlani, V., Xu, X., Blauw, J., Sudarshi, S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  31. Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. Haskell-Luevano, C., Hendrata, S., North, C., Sawyer, T.K., Hadley, M.E., Hruby, V.J., Dickinson, C., Gantz, I. J. Med. Chem. (1997) [Pubmed]
  32. Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach. Tian, X., Field, T.B., Switzer, A.G., Mazur, A.W., Ebetino, F.H., Wos, J.A., Berberich, S.M., Jayasinghe, L.R., Obringer, C.M., Dowty, M.E., Pinney, B.B., Farmer, J.A., Crossdoersen, D., Sheldon, R.J. J. Med. Chem. (2006) [Pubmed]
  33. Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors. Chai, B.X., Pogozheva, I.D., Lai, Y.M., Li, J.Y., Neubig, R.R., Mosberg, H.I., Gantz, I. Biochemistry (2005) [Pubmed]
  34. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Beaumont, K.A., Shekar, S.N., Shekar, S.L., Newton, R.A., James, M.R., Stow, J.L., Duffy, D.L., Sturm, R.A. Hum. Mol. Genet. (2007) [Pubmed]
  35. Contribution of melanocortin receptor exoloops to Agouti-related protein binding. Yang, Y.K., Dickinson, C.J., Zeng, Q., Li, J.Y., Thompson, D.A., Gantz, I. J. Biol. Chem. (1999) [Pubmed]
  36. The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation. Abdel-Malek, Z., Scott, M.C., Suzuki, I., Tada, A., Im, S., Lamoreux, L., Ito, S., Barsh, G., Hearing, V.J. Pigment Cell Res. (2000) [Pubmed]
  37. Thyrotropin releasing hormone (TRH) selectively binds and activates the melanocortin 1 receptor. Schiöth, H.B., Prusis, P., Muceniece, R., Mutulis, F., Mutule, I., Wikberg, J.E. Peptides (1999) [Pubmed]
  38. Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes. Schiöth, H.B., Mutulis, F., Muceniece, R., Prusis, P., Wikberg, J.E. Eur. J. Pharmacol. (1998) [Pubmed]
  39. Cell Signaling and Trafficking of Human Melanocortin Receptors in Real Time Using Two-photon Fluorescence and Confocal Laser Microscopy: Differentiation of Agonists and Antagonists. Cai, M., Varga, E.V., Stankova, M., Mayorov, A., Perry, J.W., Yamamura, H.I., Trivedi, D., Hruby, V.J. Chemical biology & drug design (2006) [Pubmed]
  40. The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors. Breit, A., Wolff, K., Kalwa, H., Jarry, H., B??ch, T., Gudermann, T. J. Biol. Chem. (2006) [Pubmed]
  41. Melanocortin-1 receptor (MC1R) gene variants and dysplastic nevi modify penetrance of CDKN2A mutations in French melanoma-prone pedigrees. Chaudru, V., Laud, K., Avril, M.F., Minière, A., Chompret, A., Bressac-de Paillerets, B., Demenais, F. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  42. Neuropathic pain: a possible role for the melanocortin system? Vrinten, D.H., Kalkman, C.J., Adan, R.A., Gispen, W.H. Eur. J. Pharmacol. (2001) [Pubmed]
  43. Receptor binding affinities and biological activities of linear and cyclic melanocortins in B16 murine melanoma cells expressing the native MC1 receptor. Sahm, U.G., Olivier, G.W., Branch, S.K., Moss, S.H., Pouton, C.W. J. Pharm. Pharmacol. (1996) [Pubmed]
  44. Genetic association and cellular function of MC1R variant alleles in human pigmentation. Sturm, R.A., Duffy, D.L., Box, N.F., Newton, R.A., Shepherd, A.G., Chen, W., Marks, L.H., Leonard, J.H., Martin, N.G. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  45. Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity. Yang, Y., Chen, M., Lai, Y., Gantz, I., Georgeson, K.E., Harmon, C.M. J. Biol. Chem. (2002) [Pubmed]
  46. High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein. McNulty, J.C., Thompson, D.A., Bolin, K.A., Wilken, J., Barsh, G.S., Millhauser, G.L. Biochemistry (2001) [Pubmed]
  47. ACTH1-17 is a more potent agonist at the human MC1 receptor than alpha-MSH. Tsatmali, M., Yukitake, J., Thody, A.J. Cell. Mol. Biol. (Noisy-le-grand) (1999) [Pubmed]
  48. Molecular cloning of a novel human melanocortin receptor. Chhajlani, V., Muceniece, R., Wikberg, J.E. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  49. Distribution of cDNA for melanocortin receptor subtypes in human tissues. Chhajlani, V. Biochem. Mol. Biol. Int. (1996) [Pubmed]
  50. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Mogil, J.S., Wilson, S.G., Chesler, E.J., Rankin, A.L., Nemmani, K.V., Lariviere, W.R., Groce, M.K., Wallace, M.R., Kaplan, L., Staud, R., Ness, T.J., Glover, T.L., Stankova, M., Mayorov, A., Hruby, V.J., Grisel, J.E., Fillingim, R.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  51. Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk. Beaumont, K.A., Newton, R.A., Smit, D.J., Leonard, J.H., Stow, J.L., Sturm, R.A. Hum. Mol. Genet. (2005) [Pubmed]
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