Future Vistas

  • Roger D. Cone
Part of the The Receptors book series (REC)


The cloning of the genes for the melanocortin receptors (Chapter 7) and of the agouti proteins (Chapter 14), as well as the identification of melanocortin receptor subtype specific agonists and antagonists (Chapter 8) have produced some powerful new tools for the study of the melanocortin physiology. These advances, as well as advances in understanding the physiological roles of the melanocortins, appear to be responsible for a dramatic ten-fold increase in publications on the topic over the last five years (Fig. 1), at least as searched under the keyword “melanocortin.” The finding of a role for the MC4-R in energy homeostasis has, for the first time, attracted a very significant effort in the area from the pharmaceutical industry as well. One industry-watcher has told me that there are now about 40 biotechnology and pharmaceutical companies doing some sort of research on the MC4-R for the treatment of obesity.


Energy Homeostasis Coat Color Exocrine Gland Melanocortin Receptor Agouti Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Searle, A. G. (1968) Comparative Genetics of Coat Colors in Mammals Logos Press, London.Google Scholar
  2. 2.
    Klungland, H., Vage, D. I., Gomez-Raya, L., Adelsteinsson, S., and Lien, S. (1995) The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination. Mamm. Genome 6, 636–639.PubMedCrossRefGoogle Scholar
  3. 3.
    Robbins, L. S., Nadeau, J. H., Johnson, K. R., Kelly, M. A., Roselli-Rehfuss, L., Baack, E., Mountjoy, K. G., and Cone, R. D. (1993) Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827–834.PubMedCrossRefGoogle Scholar
  4. 4.
    Vage, D., Klungland, H., Lu, D., and Cone, R. (1999) Molecular and pharmacological characterization of dominantblack coat color in sheep. Mamm. Genome 10, 39–43.PubMedCrossRefGoogle Scholar
  5. 5.
    Vage, D. I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., and Cone, R.D. (1997) A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes. Nat. Genet. 15, 311–315.CrossRefGoogle Scholar
  6. 6.
    Lyon, M. F. (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373.PubMedCrossRefGoogle Scholar
  7. 7.
    Kapas, S., Cammas, F. M., Hinson, J. P., and Clark, A. J. L. (1996) Agonist and receptor binding properties of adrenocorticotropin peptides using the cloned mouse adrenocorticotropin receptor expressed in a stably transfected HeLa cell line. Endocrinology 137, 3291–3294.PubMedCrossRefGoogle Scholar
  8. 8.
    Ni, X.-P., Kesterson, R. A., Sharma, S. D., Hruby, V. J., Cone, R. D., Wiedemann, E., and Humphreys, M. H. (1998) Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists. Am. J. Physiol. 274, R931 - R938.PubMedGoogle Scholar
  9. 9.
    Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson, S. J., Del Valle, J., and Yamada, T. (1993) Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246–8250.PubMedGoogle Scholar
  10. 10.
    Roselli-Rehfuss, L., Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., Low, M. J., Tatro, J. B., Entwistle, M. L., Simerly, R., and Cone, R. D. (1993) Identification of a receptor for y-MSH and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. U. S. A. 90, 8856–8860.PubMedCrossRefGoogle Scholar
  11. 11.
    Mizuno, T. M. and Mobbs, C. V. (1999) Hypothalamic agouti-related messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817.PubMedCrossRefGoogle Scholar
  12. 12.
    Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., and Barsh, G. S. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–137.PubMedCrossRefGoogle Scholar
  13. 13.
    Shutter, J. R., Graham, M., Kinsey, A. C., Scully, S., Luthy, R., and Stark, K. L. (1997) Hypothalamic expression of ART, a novel gene related to agouti, is upregulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602.PubMedCrossRefGoogle Scholar
  14. 14.
    Fong, T. M., Mao, C., MacNeil, C., Kalyani, R., Smith, T., Weinberg, D., Tota, M. R., and Van der Ploeg, L. H. (1997) ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem. Biophys. Res. Commun. 237, 629–631.PubMedCrossRefGoogle Scholar
  15. 15.
    Graham, M., Shuttre, J. R., Sarmiento, U., Sarosi, I., and Stark, K. L. (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat. Genet. 17, 273–274.PubMedCrossRefGoogle Scholar
  16. 16.
    Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., Smith, F. J., Campfield, L. A., Burn, P., and Lee, F. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141.PubMedCrossRefGoogle Scholar
  17. 17.
    Marsh, D. J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K. A., Fisher, S. L., Burn, P., and Palmiter, R. D. (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat. Genet. 21, 119–122.PubMedCrossRefGoogle Scholar
  18. 18.
    Vaisse, C., Clement, K., Guy-Grand, B., and Froguel, P. (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114.PubMedCrossRefGoogle Scholar
  19. 19.
    Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., and O’Rahilly, S. (1998) A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112.PubMedCrossRefGoogle Scholar
  20. 20.
    Li, S.-J., Varga, K., Archer, P., Hruby, V. J., Sharma, S. D., Kesterson, R. A., Cone, R. D., and Kunos, G. (1996) Melanocortin antagonists define two distinct pathways of cardiovascular control by a-and y-melanopcyte-stimulating hormones. J. Neurosci. 16, 5182–5188.PubMedGoogle Scholar
  21. 21.
    Huang, Q.-H., Entwistle, M. L., Alvaro, J. D., Duman, R. S., Hruby, V. J., and Tatro, J. B. (1997) Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever. J. Neurosci. 17, 3343–3351.PubMedGoogle Scholar
  22. 22.
    Von Frijtag, J. C., Croiset, G., Gispen, W. H., Adan, R. A., and Wiegant, V. M. (1998) The role of central melanocortin receptors in the activation of the hypothalamus-pituitary-adrenal-axis and the induction of excessive grooming. Br. J. Pharmacol. 123, 1503–1508.CrossRefGoogle Scholar
  23. 23.
    Chen, W., Kelly, M. A., Opitz-Araya, X., Thomas, R. E., Low, M. J., and Cone, R. D. (1997) Exocrine gland dysfunction in MC5-R deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 91, 789–798.PubMedCrossRefGoogle Scholar
  24. 24.
    van der Kraan, M., Adan, R. A. H., Entwistle, M. L., Gispen, W. H., Burbach, J. P. H., and Tatro, J. B. (1998) Expression of melanocortin-5 receptor in secretory epithelia supports a functional role in exocrine and endocrine glands. Endocrinology 139, 2348–2355.PubMedCrossRefGoogle Scholar
  25. 25.
    Fathi, Z., Iben, L. G., and Parker, E. M. (1995) Cloning, expression, and tissue distribution of a fifth melanocortin receptor subtype. Neurochem. Res. 20, 107–113.PubMedCrossRefGoogle Scholar
  26. 26.
    Labbe, O., Desarnaud, F., Eggerickx, D., Vassart, G., and Parmentier, M. (1994) Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry 33, 4543–4549.PubMedCrossRefGoogle Scholar
  27. 27.
    Kraan, v. d., Tatro, J. B., Entwistle, M. L., Brakkee, J. H., Burbach, J. P. H., Adan, R. A. H., and Gispen, W. H. (1999) Expression of melanocortin receptors and proopiomelanocortin in the rat spinal cord in relation to the neurotrophic effects of melanocortins. Mol. Brain Res. 63, 276–286.PubMedCrossRefGoogle Scholar
  28. 28.
    Lane, P. W. (1960) New mouse mutants. Mouse News Lett. 22, 35.Google Scholar
  29. 29.
    Lane, P. W. and Green, M. C. (1960) Mahogany, a recessive color mutation in linkage group V of the mouse. J. Hered. 51, 228–230.Google Scholar
  30. 30.
    Mather, K. and North, S. B. (1940) Umbrous: a case of dominance modification in mice. J. Genet. 40, 229–241.CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2000

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  • Roger D. Cone

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