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Gene Review

MC4R  -  melanocortin 4 receptor

Homo sapiens

Synonyms: MC4-R, Melanocortin receptor 4
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Disease relevance of MC4R

  • Mutations in MC4R are the most common genetic cause of obesity [1].
  • These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight [2].
  • In particular, we found no evidence for an increased rate of binge-eating behavior in obese carriers of MC4R variants [3].
  • We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study [4].
  • In addition, complete MC4R deficiency is not a cause of relative hyperinsulinemia as recently observed in children with heterozygous MC4R mutations [5].

Psychiatry related information on MC4R


High impact information on MC4R


Chemical compound and disease context of MC4R

  • Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM [13].
  • To determine whether MC4R has a role in causing severe obesity in Pima Indians, we sequenced the coding region of this gene in 426 full-heritage, non-first-degree related, adult Pima Indians (300 severely obese and 126 nondiabetic nonobese control subjects) [14].
  • In our study, we addressed the hypothesis that a G-->A substitution at codon 103 (Val-103Ile) of the MC4R gene influences abdominal obesity, insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol [15].
  • Ten structurally similar melanocortin subtype-4 receptor (MC4R) ligands from an aryl piperazine chemical platform were evaluated in female Fischer 344 rats to assess the toxicity of this class of compounds [16].
  • This regulation apparently requires genomic regulatory sequences because Dex did not increase MC4 receptor expression or signaling in CHO cells expressing the MC4 receptor under the control of a cytomegalovirus promoter [17].

Biological context of MC4R


Anatomical context of MC4R

  • Melancortin agonists stimulate cAMP in a concentration-dependent manner in both astrocytes and human embryonic kidney cells recombinantly expressing rat MC4R (HEK-rMC4R), however, the relative potency and intrinsic activity of both small molecule and peptide agonists are reduced in the native system [20].
  • Considering the tissue distribution of the MCRs, there are two distinctions between mammals and fish: where in mammals the MC4R is exclusively expressed in the central nervous system, in the fish species examined so far it is also peripherally expressed [21].
  • All the subtypes except MC4R could be detected in testis [22].
  • Immunofluorescence studies showed that the mutant proteins were expressed and localized in the intracellular compartment but absent from the plasma membrane, suggesting that these mutations disrupted the proper cellular transport of MC4R [23].
  • We then addressed the possible mechanisms underlying the desensitization using HEK293 and COS-1 cells transfected with hemagglutinin-tagged human MC4R [24].

Associations of MC4R with chemical compounds

  • Substitutions of the extracytoplasmic NH2 terminus and the first extracytoplasmic loop (exoloop) of the MC4R with homologous domains of the MC1R had no effect on AGRP (87-132) binding affinity or inhibitory activity (the ability to inhibit melanocortin-stimulated cAMP generation) [25].
  • STUDY DESIGN: Direct sequencing of the MC4R encoding sequence and single-strand polymorphism conformation analysis of AGRP and alpha MSH genes were performed in 63 severely obese children [26].
  • Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands [27].
  • For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors [28].
  • Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R [29].
  • The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R [30].

Physical interactions of MC4R


Regulatory relationships of MC4R

  • These mutations suggest the critical role of central signaling systems composed of leptin/leptin receptor and alpha-melanocyte stimulating hormone/MC4-R in human energy homeostasis [32].
  • NDP-alpha MSH induced a time-dependent internalization of MC4-R that was partially prevented by AgRP [33].

Other interactions of MC4R

  • Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R [18].
  • This report provides the details of the molecular recognition of SHU9119 antagonism at hMC4R and shows that amino acid Leu(133) of hMC4R plays a key role in melanocortin receptor subtype specificity [6].
  • The anatomical characterization shows that the MC2R is expressed in the brain in addition to the head-kidney, whereas the MC4R and MC5R are found in both brain regions and peripheral tissues [34].
  • Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects [35].
  • By means of RT-PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable [36].

Analytical, diagnostic and therapeutic context of MC4R


  1. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. Srinivasan, S., Lubrano-Berthelier, C., Govaerts, C., Picard, F., Santiago, P., Conklin, B.R., Vaisse, C. J. Clin. Invest. (2004) [Pubmed]
  2. AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Nijenhuis, W.A., Oosterom, J., Adan, R.A. Mol. Endocrinol. (2001) [Pubmed]
  3. Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations. Hebebrand, J., Geller, F., Dempfle, A., Heinzel-Gutenbrunner, M., Raab, M., Gerber, G., Wermter, A.K., Horro, F.F., Blundell, J., Schäfer, H., Remschmidt, H., Herpertz, S., Hinney, A. Mol. Psychiatry (2004) [Pubmed]
  4. Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. Hinney, A., Hohmann, S., Geller, F., Vogel, C., Hess, C., Wermter, A.K., Brokamp, B., Goldschmidt, H., Siegfried, W., Remschmidt, H., Schäfer, H., Gudermann, T., Hebebrand, J. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  5. A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. Lubrano-Berthelier, C., Le Stunff, C., Bougnères, P., Vaisse, C. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  6. 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]
  7. Melanocortin-4 receptor gene and physical activity in the Québec Family Study. Loos, R.J., Rankinen, T., Tremblay, A., Pérusse, L., Chagnon, Y., Bouchard, C. International journal of obesity (2005) (2005) [Pubmed]
  8. Appetite control and reproduction: leptin and beyond. Small, C.J., Stanley, S.A., Bloom, S.R. Seminars in reproductive medicine. (2002) [Pubmed]
  9. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Yeo, G.S., Farooqi, I.S., Aminian, S., Halsall, D.J., Stanhope, R.G., O'Rahilly, S. Nat. Genet. (1998) [Pubmed]
  10. Haploinsufficiency of the melanocortin-4 receptor: part of a thrifty genotype? Cone, R.D. J. Clin. Invest. (2000) [Pubmed]
  11. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Geller, F., Reichwald, K., Dempfle, A., Illig, T., Vollmert, C., Herpertz, S., Siffert, W., Platzer, M., Hess, C., Gudermann, T., Biebermann, H., Wichmann, H.E., Schäfer, H., Hinney, A., Hebebrand, J. Am. J. Hum. Genet. (2004) [Pubmed]
  12. Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. Lubrano-Berthelier, C., Durand, E., Dubern, B., Shapiro, A., Dazin, P., Weill, J., Ferron, C., Froguel, P., Vaisse, C. Hum. Mol. Genet. (2003) [Pubmed]
  13. Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians. Hani, E.H., Dupont, S., Durand, E., Dina, C., Gallina, S., Gantz, I., Froguel, P. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  14. Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. Ma, L., Tataranni, P.A., Bogardus, C., Baier, L.J. Diabetes (2004) [Pubmed]
  15. A missense mutation in the human melanocortin-4 receptor gene in relation to abdominal obesity and salivary cortisol. Rosmond, R., Chagnon, M., Bouchard, C., Björntorp, P. Diabetologia (2001) [Pubmed]
  16. Gastric mucosal damage following repeat administration of melanocortin subtype-4 receptor ligands to Fischer 344 rats. Williams, T.M., Donnelly, K.B. Toxicologic pathology (2006) [Pubmed]
  17. Regulation of endogenous melanocortin-4 receptor expression and signaling by glucocorticoids. Sebag, J.A., Hinkle, P.M. Endocrinology (2006) [Pubmed]
  18. 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]
  19. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Xiang, Z., Litherland, S.A., Sorensen, N.B., Proneth, B., Wood, M.S., Shaw, A.M., Millard, W.J., Haskell-Luevano, C. Biochemistry (2006) [Pubmed]
  20. Identification of differential melanocortin 4 receptor agonist profiles at natively expressed receptors in rat cortical astrocytes and recombinantly expressed receptors in human embryonic kidney cells. Selkirk, J.V., Nottebaum, L.M., Lee, J., Yang, W., Foster, A.C., Lechner, S.M. Neuropharmacology (2007) [Pubmed]
  21. Molecular biology and physiology of the melanocortin system in fish: a review. Metz, J.R., Peters, J.J., Flik, G. Gen. Comp. Endocrinol. (2006) [Pubmed]
  22. Distribution of cDNA for melanocortin receptor subtypes in human tissues. Chhajlani, V. Biochem. Mol. Biol. Int. (1996) [Pubmed]
  23. Functional characterization of mutations in melanocortin-4 receptor associated with human obesity. Ho, G., MacKenzie, R.G. J. Biol. Chem. (1999) [Pubmed]
  24. Regulation of melanocortin-4 receptor signaling: agonist-mediated desensitization and internalization. Shinyama, H., Masuzaki, H., Fang, H., Flier, J.S. Endocrinology (2003) [Pubmed]
  25. 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]
  26. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. Dubern, B., Clément, K., Pelloux, V., Froguel, P., Girardet, J.P., Guy-Grand, B., Tounian, P. J. Pediatr. (2001) [Pubmed]
  27. Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3 receptor selectivity. Nickolls, S.A., Cismowski, M.I., Wang, X., Wolff, M., Conlon, P.J., Maki, R.A. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  28. Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of gamma-MSH analogs substituted with L-alanine. Grieco, P., Balse-Srinivasan, P., Han, G., Weinberg, D., MacNeil, T., Van der Ploeg, L.H., Hruby, V.J. J. Pept. Res. (2002) [Pubmed]
  29. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Lee, Y.S., Challis, B.G., Thompson, D.A., Yeo, G.S., Keogh, J.M., Madonna, M.E., Wraight, V., Sims, M., Vatin, V., Meyre, D., Shield, J., Burren, C., Ibrahim, Z., Cheetham, T., Swift, P., Blackwood, A., Hung, C.C., Wareham, N.J., Froguel, P., Millhauser, G.L., O'Rahilly, S., Farooqi, I.S. Cell metabolism. (2006) [Pubmed]
  30. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. Hainerová, I., Larsen, L.H., Holst, B., Finková, M., Hainer, V., Lebl, J., Hansen, T., Pedersen, O. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  31. Effects of pH, salt and time on ligand binding properties of overexpressed melanocortin 4 receptor. Dolby, V., Lundqvist, A., Fröberg, T., Lüllau, E., Shaw, J., Tjerneld, F., Cronet, P. J. Biochem. Biophys. Methods (2004) [Pubmed]
  32. Monogenic disorders of obesity and body fat distribution. Chen, D., Garg, A. J. Lipid Res. (1999) [Pubmed]
  33. Characterization of cell lines stably expressing human normal or mutated EGFP-tagged MC4R. Blondet, A., Doghman, M., Rached, M., Durand, P., Bégeot, M., Naville, D. J. Biochem. (2004) [Pubmed]
  34. The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. Klovins, J., Haitina, T., Fridmanis, D., Kilianova, Z., Kapa, I., Fredriksson, R., Gallo-Payet, N., Schiöth, H.B. Mol. Biol. Evol. (2004) [Pubmed]
  35. Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands. Pritchard, L.E., Armstrong, D., Davies, N., Oliver, R.L., Schmitz, C.A., Brennand, J.C., Wilkinson, G.F., White, A. J. Endocrinol. (2004) [Pubmed]
  36. Gamma-MSH peptides in the pituitary: effects, target cells, and receptors. Denef, C., Lu, J., Swinnen, E. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  37. Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Elmquist, J.K. Int. J. Obes. Relat. Metab. Disord. (2001) [Pubmed]
  38. Low frequency of melanocortin-4 receptor (MC4R) mutations in a Mediterranean population with early-onset obesity. Miraglia Del Giudice, E., Cirillo, G., Nigro, V., Santoro, N., D'Urso, L., Raimondo, P., Cozzolino, D., Scafato, D., Perrone, L. Int. J. Obes. Relat. Metab. Disord. (2002) [Pubmed]
  39. Assignment of the melanocortin 4 receptor (MC4R) gene to human chromosome band 18q22 by in situ hybridisation and radiation hybrid mapping. Sundaramurthy, D., Campbell, D.A., Leek, J.P., Markham, A.F., Pieri, L.F. Cytogenet. Cell Genet. (1998) [Pubmed]
  40. The role of the DRY motif of human MC4R for receptor activation. Yamano, Y., Kamon, R., Yoshimizu, T., Toda, Y., Oshida, Y., Chaki, S., Yoshioka, M., Morishima, I. Biosci. Biotechnol. Biochem. (2004) [Pubmed]
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