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Gene Review

MC3R  -  melanocortin 3 receptor

Homo sapiens

Synonyms: BMIQ9, MC3, MC3-R, Melanocortin receptor 3, OB20, ...
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Disease relevance of MC3R

  • At least one specific mutation of MC3R has been identified to be associated with human obesity [1].
  • The specific melanocortin receptors, MC3R and MC4R, are directly linked to metabolism and body weight control [2].
  • In contrast, no significant associations of MC3R variants with obesity have been detected, although a significant association with hyperinsulinemia has been reported in Caucasian populations [3].
  • Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians [4].
  • The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001) [5].
  • These results suggest a gene-diet interaction between the MC3R C17A and G241A variants and a weight loss program for the ability to lose weight in childhood obesity [6].

Psychiatry related information on MC3R


High impact information on MC3R

  • Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders [8].
  • This melanocortin receptor (MC3-R) is found in neurons of the arcuate nucleus known to express proopiomelanocortin (POMC) and in a subset of the nuclei to which these neurons send projections [9].
  • The MC3-R is 43% identical to the MSH receptor present in melanocytes and is strongly coupled to adenylyl cyclase [9].
  • Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R [10].
  • Both human linkage studies and MC3R knockout mouse models suggest that the MC3R may play an important role in energy homeostasis [11].

Chemical compound and disease context of MC3R


Biological context of MC3R


Anatomical context of MC3R

  • The melanocortin 3 receptor (MC3-R), characterized previously, was found to be expressed in arcuate nucleus neurons and in a subset of their presumptive terminal fields but in few regions of the brainstem [16].
  • Unlike the MC3-R, MC4-R mRNA is found in both parvicellular and magnocellular neurons of the paraventricular nucleus of the hypothalamus, suggesting a role in the central control of pituitary function [16].
  • Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R [17].
  • PT-141, a synthetic peptide analogue of alpha-MSH, is an agonist at melanocortin receptors including the MC3R and MC4R, which are expressed primarily in the central nervous system [18].
  • These data suggest that the GH3 cell line does not mediate the effect of gamma3MSH through the MC3 receptor [19].

Associations of MC3R with chemical compounds

  • It has been shown by extensive studies that alpha-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R [14].
  • Mutation of Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine) selectively decreased affinity and potency of MC4R-selective ligands [20].
  • Together, MC3-R and/or MC-4R mRNA are found in every nucleus reported to bind MSH in the adult rat brain and define neuronal circuitry known to be involved in the control of diverse neuroendocrine and autonomic functions [16].
  • AgRP acting via the MC3-R or MC4-R may have an inhibitory paracrine role, blocking alpha-MSH-induced corticosterone secretion [21].
  • These data indicate that the hMC3R is coupled to both cAMP and inositol phospholipid/Ca(2+)-mediated post-receptor signaling systems and that the latter response is regulated by protein kinase A activity [22].

Physical interactions of MC3R


Regulatory relationships of MC3R


Other interactions of MC3R

  • The system comprises alpha-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R) [25].
  • The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity [26].
  • In total, our results suggest that a differential receptor-ligand interaction is involved and that the relative interactions of MC3R and MC4R with G protein are possibly quantitatively and qualitatively different [27].
  • Alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits feeding through melanocrtin 3 and 4 receptors (MC3-R and MC4-R) as an endogenous agonist [28].
  • However, unlike the LMNA 1908C/T genetic variation, the MC3R 241G/A genetic variation was significantly associated with hyperleptinemia and huperinsulinemia in obese subjects, and there was evidence of interaction between this polymorphism and fat mass or BMI in predicting hyperinsulinemia [3].

Analytical, diagnostic and therapeutic context of MC3R


  1. Molecular characterization of human melanocortin-3 receptor ligand-receptor interaction. Chen, M., Aprahamian, C.J., Celik, A., Georgeson, K.E., Garvey, W.T., Harmon, C.M., Yang, Y. Biochemistry (2006) [Pubmed]
  2. Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors. Jackson, P.J., Yu, B., Hunrichs, B., Thompson, D.A., Chai, B., Gantz, I., Millhauser, G.L. Peptides (2005) [Pubmed]
  3. The Val81 missense mutation of the melanocortin 3 receptor gene, but not the 1908c/T nucleotide polymorphism in lamin A/C gene, is associated with hyperleptinemia and hyperinsulinemia in obese Greek caucasians. Yiannakouris, N., Melistas, L., Kontogianni, M., Heist, K., Mantzoros, C.S. J. Endocrinol. Invest. (2004) [Pubmed]
  4. 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]
  5. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Rossi, M., Kim, M.S., Morgan, D.G., Small, C.J., Edwards, C.M., Sunter, D., Abusnana, S., Goldstone, A.P., Russell, S.H., Stanley, S.A., Smith, D.M., Yagaloff, K., Ghatei, M.A., Bloom, S.R. Endocrinology (1998) [Pubmed]
  6. Effect of the melanocortin-3 receptor C17A and G241A variants on weight loss in childhood obesity. Santoro, N., Perrone, L., Cirillo, G., Raimondo, P., Amato, A., Brienza, C., Del Giudice, E.M. Am. J. Clin. Nutr. (2007) [Pubmed]
  7. Mutation analysis of the agouti related protein promoter region and the melanocortin-3 receptor in anorexia nervosa patients. de Krom, M., de Rijke, C.E., Hendriks, J., van Engeland, H., van Elburg, A.A., Adan, R.A. Psychiatr. Genet. (2005) [Pubmed]
  8. Targeting melanocortin receptors as a novel strategy to control inflammation. Catania, A., Gatti, S., Colombo, G., Lipton, J.M. Pharmacol. Rev. (2004) [Pubmed]
  9. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Roselli-Rehfuss, L., Mountjoy, K.G., Robbins, L.S., Mortrud, M.T., Low, M.J., Tatro, J.B., Entwistle, M.L., Simerly, R.B., Cone, R.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  10. 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]
  11. Co-occurrence of two partially inactivating polymorphisms of MC3R is associated with pediatric-onset obesity. Feng, N., Young, S.F., Aguilera, G., Puricelli, E., Adler-Wailes, D.C., Sebring, N.G., Yanovski, J.A. Diabetes (2005) [Pubmed]
  12. Leptin-like effects of MTII are augmented in MSG-obese rats. Kim, Y.W., Choi, D.W., Park, Y.H., Huh, J.Y., Won, K.C., Choi, K.H., Park, S.Y., Kim, J.Y., Lee, S.K. Regul. Pept. (2005) [Pubmed]
  13. 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]
  14. Structure-activity relationships of novel cyclic alpha-MSH/beta-MSH hybrid analogues that lead to potent and selective ligands for the human MC3R and human MC5R. Balse-Srinivasan, P., Grieco, P., Cai, M., Trivedi, D., Hruby, V.J. J. Med. Chem. (2003) [Pubmed]
  15. A +2138InsCAGACC polymorphism of the melanocortin receptor 3 gene is associated in human with fat level and partitioning in interaction with body corpulence. Boucher, N., Lanouette, C.M., Larose, M., Pérusse, L., Bouchard, C., Chagnon, Y.C. Mol. Med. (2002) [Pubmed]
  16. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mountjoy, K.G., Mortrud, M.T., Low, M.J., Simerly, R.B., Cone, R.D. Mol. Endocrinol. (1994) [Pubmed]
  17. 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]
  18. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Molinoff, P.B., Shadiack, A.M., Earle, D., Diamond, L.E., Quon, C.Y. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  19. Stimulation of intracellular free calcium in GH3 cells by gamma3-melanocyte-stimulating hormone. Involvement of a novel melanocortin receptor? Langouche, L., Roudbaraki, M., Pals, K., Denef, C. Endocrinology (2001) [Pubmed]
  20. 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]
  21. Agouti-related protein has an inhibitory paracrine role in the rat adrenal gland. Dhillo, W.S., Small, C.J., Gardiner, J.V., Bewick, G.A., Whitworth, E.J., Jethwa, P.H., Seal, L.J., Ghatei, M.A., Hinson, J.P., Bloom, S.R. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  22. Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor. Konda, Y., Gantz, I., DelValle, J., Shimoto, Y., Miwa, H., Yamada, T. J. Biol. Chem. (1994) [Pubmed]
  23. Photoperiod regulates growth, puberty and hypothalamic neuropeptide and receptor gene expression in female Siberian hamsters. Adam, C.L., Moar, K.M., Logie, T.J., Ross, A.W., Barrett, P., Morgan, P.J., Mercer, J.G. Endocrinology (2000) [Pubmed]
  24. Arthritic diseases: melanocortin type 3 receptor agonists as potential therapeutics. Getting, S.J., Perretti, M. Current opinion in investigational drugs (London, England : 2000) (2001) [Pubmed]
  25. 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]
  26. 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]
  27. Differential regulation of cAMP-mediated gene transcription and ligand selectivity by MC3R and MC4R melanocortin receptors. Lee, E.J., Lee, S.H., Jung, J.W., Lee, W., Kim, B.J., Park, K.W., Lim, S.K., Yoon, C.J., Baik, J.H. Eur. J. Biochem. (2001) [Pubmed]
  28. The physiological function of the agouti-related peptide gene: the control of weight and metabolic rate. Mizuno, T.M., Makimura, H., Mobbs, C.V. Ann. Med. (2003) [Pubmed]
  29. Melanocortin 3 receptor (MC3R) gene variants in extremely obese women. Li, W.D., Joo, E.J., Furlong, E.B., Galvin, M., Abel, K., Bell, C.J., Price, R.A. Int. J. Obes. Relat. Metab. Disord. (2000) [Pubmed]
  30. MC3-R as a novel target for antiinflammatory therapy. Getting, S.J., Perretti, M. Drug News Perspect. (2000) [Pubmed]
  31. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Getting, S.J., Christian, H.C., Flower, R.J., Perretti, M. Arthritis Rheum. (2002) [Pubmed]
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