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Gene Review

Mc2r  -  melanocortin 2 receptor

Mus musculus

Synonyms: ACTH receptor, ACTH-R, ACTHR, Acthr, Adrenocorticotropic hormone receptor, ...
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Disease relevance of Mc2r


Psychiatry related information on Mc2r


High impact information on Mc2r

  • In addition to their antimicrobial and cytotoxic properties, some defensins act as opsonins, while others inhibit protein kinase C, bind specifically to the ACTH receptor and block steroidogenesis or act as selective chemoattractants for monocytes [6].
  • That this binding might result from one peptide being an "internal image" of the other was strongly suggested by the observation that antibody to the peptide that was encoded by the complementary RNA for ACTH recognized the adrenal cell ACTH receptor [7].
  • Mutation of the PPRE to prevent PPARgamma/RXRalpha binding resulted in a complete abrogation of the pMC2-R(-112/+105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte [8].
  • These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis [8].
  • A mutant MC2R in which the single consensus PKA phosphorylation site has been mutated (S208A) when expressed in MC2R-negative Y6 cells is also unable to desensitize [9].

Chemical compound and disease context of Mc2r

  • None of the antisera displayed any effect in these assays, nor did they bind to blotted MSH/ACTH receptor protein from Cloudman S91 melanoma cells or to ACTH antibodies [10].

Biological context of Mc2r

  • The analysis of the cDNA 5'-end showed an untranslated region of 321 bp, and the ACTH-R gene was demonstrated to be composed of two exons of 113 and 112 bp lying upstream of the single coding exon [11].
  • CONCLUSION: MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH [12].
  • SF1(A172) and SF1(S172) exhibit little or no difference in transcriptional activity in SF1-dependent reporter gene assays, suggesting that SF1(S172) per se is not directly responsible for the loss of MC2R expression [13].
  • In this study, we show that a luciferase reporter plasmid driven by 1,800 bp of the proximal promoter region of the MC2R was expressed poorly in the mutant cells compared with parent Y1 cells [14].
  • In Crhr1-/- mice, intravenous ACTH administration failed to stimulate corticosterone secretion despite a significant upregulation of ACTH receptor mRNA levels in the adrenal cortex of these mutants [15].

Anatomical context of Mc2r


Associations of Mc2r with chemical compounds


Physical interactions of Mc2r

  • We have used the chromatin immunoprecipitation assay to examine the temporal formation of ACTH-dependent transcription complexes on the Mc2r gene promoter [25].
  • Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter [25].

Enzymatic interactions of Mc2r


Regulatory relationships of Mc2r

  • We have described a family of adrenocortical tumor cell mutants (including clones OS3, Y6, and 10r9) that are resistant to ACTH because they fail to express the gene encoding the ACTH receptor (MC2R) [13].
  • A dominant negative GRK2 inhibited internalization whilst the protein kinase A (PKA) consensus site mutant MC2R (S208A) internalized normally [26].
  • ACTH induces c-fos proto-oncogene in fibroblasts expressing the ACTH receptor [27].

Other interactions of Mc2r


Analytical, diagnostic and therapeutic context of Mc2r

  • However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors [12].
  • As demonstrated by semiquantitative RT-PCR, MC2-R mRNA levels increased from E11.5 until birth, while the highest adrenal secretory protease (AsP) expression was detected at E13.5 with a decrease thereafter [30].
  • In addition, adrenocorticotropin-hormone (ACTH) receptor (melanocortin-2-receptor (MC2-R)) expression was examined by in situ hybridization (ISH) and co-localized with 3beta-HSD [30].
  • The ACTH receptor gene appears to be present in these mutants as determined by Southern blot hybridization analysis and can be activated following the growth of the mutant cells as tumors in mice, suggesting that the ACTH receptor gene is modified in a reversible manner [31].
  • Immobilization stress triggered a large increase in MC-2 receptor mRNA in SCG [32].


  1. Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland. Allen, R.G., Carey, C., Parker, J.D., Mortrud, M.T., Mellon, S.H., Low, M.J. Mol. Endocrinol. (1995) [Pubmed]
  2. ACTH stimulates insulin secretion from MIN6 cells and primary mouse and human islets of Langerhans. Al-Majed, H.T., Jones, P.M., Persaud, S.J., Sugden, D., Huang, G.C., Amiel, S., Whitehouse, B.J. J. Endocrinol. (2004) [Pubmed]
  3. Adrenocortical responsiveness to adrenocorticotropic hormone is enhanced in chronically food-restricted rats. Han, E.S., Evans, T.R., Nelson, J.F. J. Nutr. (1998) [Pubmed]
  4. Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression. Zwermann, O., Beuschlein, F., Lalli, E., Klink, A., Sassone-Corsi, P., Reincke, M. Eur. J. Endocrinol. (2005) [Pubmed]
  5. Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1. Babu, P.S., Bavers, D.L., Beuschlein, F., Shah, S., Jeffs, B., Jameson, J.L., Hammer, G.D. Endocrinology (2002) [Pubmed]
  6. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Lehrer, R.I., Lichtenstein, A.K., Ganz, T. Annu. Rev. Immunol. (1993) [Pubmed]
  7. Similarity between the corticotropin (ACTH) receptor and a peptide encoded by an RNA that is complementary to ACTH mRNA. Bost, K.L., Smith, E.M., Blalock, J.E. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  8. A peroxisome proliferator-response element in the murine mc2-r promoter regulates its transcriptional activation during differentiation of 3T3-L1 adipocytes. Noon, L.A., Clark, A.J., King, P.J. J. Biol. Chem. (2004) [Pubmed]
  9. Desensitization of the Y1 cell adrenocorticotropin receptor: evidence for a restricted heterologous mechanism implying a role for receptor-effector complexes. Baig, A.H., Swords, F.M., Noon, L.A., King, P.J., Hunyady, L., Clark, A.J. J. Biol. Chem. (2001) [Pubmed]
  10. Receptor-specific antibodies by immunization with "antisense" peptides? Eberle, A.N., Drozdz, R., Baumann, J.B., Girard, J. Pept. Res. (1989) [Pubmed]
  11. The mouse adrenocorticotropin receptor gene: cloning and characterization of its promoter and evidence for a role for the orphan nuclear receptor steroidogenic factor 1. Cammas, F.M., Pullinger, G.D., Barker, S., Clark, A.J. Mol. Endocrinol. (1997) [Pubmed]
  12. ACTH 1-24 inhibits proliferation of adrenocortical tumors in vivo. Zwermann, O., Schulte, D.M., Reincke, M., Beuschlein, F. Eur. J. Endocrinol. (2005) [Pubmed]
  13. A polymorphic form of steroidogenic factor 1 associated with ACTH receptor deficiency in mouse adrenal cell mutants. Schimmer, B.P., Cordova, M., Tsao, J., Frigeri, C. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  14. Impaired steroidogenic factor 1 (NR5A1) activity in mutant Y1 mouse adrenocortical tumor cells. Frigeri, C., Tsao, J., Czerwinski, W., Schimmer, B.P. Mol. Endocrinol. (2000) [Pubmed]
  15. Expression of CRHR1 and CRHR2 in mouse pituitary and adrenal gland: implications for HPA system regulation. Müller, M.B., Preil, J., Renner, U., Zimmermann, S., Kresse, A.E., Stalla, G.K., Keck, M.E., Holsboer, F., Wurst, W. Endocrinology (2001) [Pubmed]
  16. Adrenocorticotropic hormone directly stimulates testosterone production by the fetal and neonatal mouse testis. O'Shaughnessy, P.J., Fleming, L.M., Jackson, G., Hochgeschwender, U., Reed, P., Baker, P.J. Endocrinology (2003) [Pubmed]
  17. Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. Boston, B.A., Cone, R.D. Endocrinology (1996) [Pubmed]
  18. Cloning, characterization and expression of a functional mouse ACTH receptor. Cammas, F.M., Kapas, S., Barker, S., Clark, A.J. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  19. Spatial and temporal patterns of expression of melanocortin type 2 and 5 receptors in the fetal mouse tissues and organs. Nimura, M., Udagawa, J., Hatta, T., Hashimoto, R., Otani, H. Anat. Embryol. (2006) [Pubmed]
  20. Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. Xia, Y., Wikberg, J.E. Cell Tissue Res. (1996) [Pubmed]
  21. Expressional regulation of the angiopoietin-1 and -2 and the endothelial-specific receptor tyrosine kinase Tie2 in adrenal atrophy: a study of adrenocorticotropin-induced repair. Féraud, O., Mallet, C., Vilgrain, I. Endocrinology (2003) [Pubmed]
  22. ACTH receptor-mediated induction of leukocyte cyclic AMP. Johnson, E.W., Blalock, J.E., Smith, E.M. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  23. Molecular characterization of a corticotropin (ACTH) receptor. Bost, K.L., Blalock, J.E. Mol. Cell. Endocrinol. (1986) [Pubmed]
  24. Evaluation of receptor function in ACTH-responsive and ACTH-insensitive adrenal tumor cells. Rae, P.A., Tsao, J., Schimmer, B.P. Can. J. Biochem. (1979) [Pubmed]
  25. Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation. Winnay, J.N., Hammer, G.D. Mol. Endocrinol. (2006) [Pubmed]
  26. Agonist activated adrenocorticotropin receptor internalizes via a clathrin-mediated G protein receptor kinase dependent mechanism. Baig, A.H., Swords, F.M., Szaszák, M., King, P.J., Hunyady, L., Clark, A.J. Endocr. Res. (2002) [Pubmed]
  27. ACTH induces c-fos proto-oncogene in fibroblasts expressing the ACTH receptor. Forti, F.L., Armelin, H.A. Endocr. Res. (1998) [Pubmed]
  28. Steroid receptor coactivator-1-deficient mice exhibit altered hypothalamic-pituitary-adrenal axis function. Winnay, J.N., Xu, J., O'Malley, B.W., Hammer, G.D. Endocrinology (2006) [Pubmed]
  29. The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1-24) ligand structure activity relationships at the melanocortin-2 receptor. Haskell-Luevano, C., Todorovic, A., Gridley, K., Sorenson, N., Irani, B., Xiang, Z. Endocr. Res. (2004) [Pubmed]
  30. Expression and spatio-temporal distribution of differentiation and proliferation markers during mouse adrenal development. Schulte, D.M., Shapiro, I., Reincke, M., Beuschlein, F. Gene Expr. Patterns (2007) [Pubmed]
  31. ACTH-receptor deficient mutants of the Y1 mouse adrenocortical tumor cell line. Schimmer, B.P., Kwan, W.K., Tsao, J., Qiu, R. Endocr. Res. (1995) [Pubmed]
  32. Adrenocorticotropic hormone (MC-2) receptor mRNA is expressed in rat sympathetic ganglia and up-regulated by stress. Nankova, B.B., Kvetnansky, R., Sabban, E.L. Neurosci. Lett. (2003) [Pubmed]
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