Advertisement

The Melanocortin-3 Receptor

  • Robert A. Kesterson
Chapter
Part of the The Receptors book series (REC)

Abstract

This chapter deals with perhaps the least understood receptor for the melanocortin peptides, that is the melanocortin-3 receptor (MC3-R). Although naturally occurring and genetically engineered mutations have provided us with insight into the function of the other known melanocortin receptors, little is known about the physiologic role of the MC3-R. Therefore, in order to further our understanding and potentially ascribe a function to the MC3-R, I will review the literature which describes the cloning and tissue-specific expression of the MC3-R gene. Particular attention will be paid to the neural expression of the MC3-R, as well as the pharmacological characterization of this receptor in vitro as a “γ-MSH” melanocortin receptor. Additionally, I will review the recent data, which describes the pharmacologic interaction of agouti and agouti-related peptide with the MC3-R. Finally, I will describe in vivo data which convincingly demonstrates one physiologic role of γ-MSH in mediating the response of reflex natriuresis. Since introduction of antagonists of the MC3-R potently block the natriuretic response induced by γ-MSH, one likely physiologic function for the MC3 receptor has thereby been identified.

Keywords

Melanocortin Receptor Chimeric Receptor Melanocortin Peptide Potential Protein Kinase Melanocortin Receptor Gene 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248–1251.PubMedCrossRefGoogle Scholar
  2. 2.
    Chhajlani, V. and Wikberg, J. E. (1992) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 309, 417–420.PubMedCrossRefGoogle Scholar
  3. 3.
    Roselli-Rehfuss, L., Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., Low, M. J., Tatro, J. B., Entwistle, M. L., Simerly, R. B., and Cone, R. D. (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. U. S. A. 90, 8856–8860.PubMedCrossRefGoogle Scholar
  4. 4.
    Gantz, I., Konda, Y., Tashiro, T., Shimoto, Y., Miwa, H., Munzert, G., Watson S. J., DelValle, J., and Yamada, T. (1993) Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 268, 8246–8250.PubMedGoogle Scholar
  5. 5.
    Desarnaud, F., Labbe, O., Eggerickx, D., Vassart, G., and Parmentier, M. (1994) Molecular cloning, functional expression and pharmacological characterization of a mouse melanocortin receptor gene. Biochem. J. 299, 367–373.PubMedGoogle Scholar
  6. 6.
    Bell, G. I., Xiang, K., Newman, M. V., Wu, S., Wright, L. G., Fajans, S. S., Spielman, R. S., and Cox, N. J. (1991) Gene for non-insulin dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc. Natl. Acad. Sci. U. S. A. 88, 1484–1488.PubMedCrossRefGoogle Scholar
  7. 7.
    Yamada, Y., Xiang, K., Bell, G. I., Seino, S., and Nishi, M. (1992) Dinucleotide repeat polymorphism in a gene on chromosome 20 encoding a G-protein coupled receptor (D20S32e). Nucleic Acids Res. 19, 2519.CrossRefGoogle Scholar
  8. 8.
    Magenis, R. E., Smith, L., Nadeau, J. H., Johnson, K. R., Mountjoy, K. G., and Cone, R. D. (1994) Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mamm. Genome 5, 503–508.PubMedCrossRefGoogle Scholar
  9. 9.
    Malafosse, A., Leboyer, M., Dulac, O., Navelet, Y., Plouin, P., Beck, C., LaklouH., Mouchnino, G., Grandscene, P., Vallee, L., Guilloud-Bataille, M., Samolyk, D., Baldy-Moulinier, M., Feingold, J., and Mallet, J. (1992) Confirmation of linkage of benign familial neonatal convulsions to D2OS 19 and D20S20. Hum. Genet. 89, 54–58.PubMedCrossRefGoogle Scholar
  10. 10.
    Biervert, C., Schroeder, B. C., Kubisch, C., et al. (1998) A potassium channel mutation in neonatal human epilepsy. Science 279, 403–406.PubMedCrossRefGoogle Scholar
  11. 11.
    Singh, N. A., Charlier, C., Stauffer, D., et al. (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nature Genet. 1, 25–29.CrossRefGoogle Scholar
  12. 12.
    O’Dowd, B. F., Hnatowich, M., Caron, M. G., Lefkowitz, R. J., and Bouvier, M. (1989) Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J. Biol. Chem. 264, 7564–7569.PubMedGoogle Scholar
  13. 13.
    Sahm, U. G., Qarawi, M. A., Olivier, G. W., Ahmed, A. R., Branch, S. K., Moss, S. H., and Pouton, C. W. (1994) The melanocortin (MC3) receptor from rat hypothalamus: photoaffinity labelling and binding of alanine-substituted alpha-MSH analogues [published erratum appears in FEBS Lett 1994 Sep 5; 351(2):295]. FEBS Lett. 350, 29–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Schioth, H. B., Muceniece, R., Wikberg, J. E., and Szardenings, M. (1996) Alternative translation initiation codon for the human melanocortin MC3 receptor does not affect the ligand binding. Eur. J. Pharmacolo. 314, 381–384.CrossRefGoogle Scholar
  15. 15.
    Jacobowitz, D. M. and O’Donohue, T. L. (1978) Alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc. Natl. Acad. Sci. U. S. A. 75, 6300–6304.PubMedCrossRefGoogle Scholar
  16. 16.
    Bronstein, D. M., Schafer, M. K., Watson, S. J., and Akil, H. (1992) Evidence that beta-endorphin is synthesized in cells in the nucleus tractus solitarius: detection of POMC mRNA. Brain Res. 587, 269–275.PubMedCrossRefGoogle Scholar
  17. 17.
    Tatro, J. B. and Entwistle, M. L. (1994) Heterogeneity of brain melanocortin receptors suggested by differential ligand binding in situ. Brain Res. 635, 148–158.PubMedCrossRefGoogle Scholar
  18. 18.
    Low, M. J., Simerly, R. B., and Cone, R. D. (1994) Receptors for the melanocortin peptides in the central nervous system. Curr. Opin. Endrocrinol. Diabetes 1, 79–88.CrossRefGoogle Scholar
  19. 19.
    Kawai, Y., Inagaki, S., Shiosaka, S., Shibasaki, T., Ling, N., Tohyama, M., and Shiotani, Y. (1984) The distribution and projection of gamma—melanocyte stimulating hormone in the rat brain: an immunohistochemical analysis. Brain Res. 297, 21–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Fodor, M., Sluiter, A., Frankhuijzen—Sierevogel, A., Wiegant, V. M., Hoogerhout, P., de Wildt, D. J., and Versteeg, D. H. (1996) Distribution of Lys—gamma 2—melanocyte—stimulating hormone— (Lys—gamma 2—MSH)—like immunoreactivity in neuronal elements in the brain and peripheral tissues of the rat. Brain Res. 731, 182–189.PubMedCrossRefGoogle Scholar
  21. 21.
    Xia, Y. and Wikberg, J. E. S. (1997) Postnatal expression of melanocortin-3 receptor in rat diencephalon and mesencephalon. Neuropharmacology 36, 217–224.PubMedCrossRefGoogle Scholar
  22. 22.
    Chhajlani, V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem. Mole. Biol. Int. 38, 73–80.Google Scholar
  23. 23.
    Klein, M. C., Hutchins, P. M., Lymangrover, J. R., and Gruber, K. A. (1985) Pressor and cardioaccelerator effects of gamma MSH and related peptides. Life Sci. 36, 769–775.PubMedCrossRefGoogle Scholar
  24. 24.
    Gruber, K. A. and Callahan, M. F. (1989) ACTH—(4–10) through gamma—MSH: evidence for a new class of central autonomic nervous system—regulating peptides. Am. J. Physiol. 257, R681 - R694.PubMedGoogle Scholar
  25. 25.
    Van Bergen, P., Janssen, P. M., Hoogerhout, P., de Wildt, D. J., and Versteeg, D. H. (1995) Cardiovascular effects of gamma—MSH/ACTH—like peptides: structure—activity relationship. Eur. J. Pharmacol. 294, 795–803.PubMedCrossRefGoogle Scholar
  26. 26.
    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 alpha—and gamma—melanocyte—stimulating hormones. J. Neurosci. 16, 5182–5188.PubMedGoogle Scholar
  27. 27.
    Konda, Y., Gantz, I., DelValle, J., Shimoto, Y., Miwa, H., and Yamada, T. (1994) Interaction of dual intracellular signaling pathways activated by the melanocortin3 receptor. J. Biol. Chem. 269, 13162–13166.PubMedGoogle Scholar
  28. 28.
    Hruby, V. J., Lu, D., Sharma, S. D., Castrucci, A. L., Kesterson, R. A., al—Obeidi, F. A., and Cone, R. D. (1995) Cyclic lactam alpha—melanotropin analogues of Ac—Nle4cyclo[AspS, c—Phe7,Lys 10] alpha—melanocyte—stimulating hormone—(4–10)—NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454–3461.Google Scholar
  29. 29.
    Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J., and Cone, R. D. (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168.PubMedCrossRefGoogle Scholar
  30. 30.
    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
  31. 31.
    Adan, R. A., Oosterom, J., Ludvigsdottir, G., Brakkee, J. H., Burbach, J. P., and Gispen, W. H. (1994) Identification of antagonists for melanocortin MC3, MC4 and MC5 receptors. Euro. J. Pharmacol. 269, 331–337.CrossRefGoogle Scholar
  32. 32.
    Lu, D., Willard, D., Patel, I. R., Kadwell, S., Overton, L., Kost, T., Luther, M., Woychik, R. P., Wilkison, W. O., and et al. (1994) Agouti protein is an antagonist of the melanocyte—stimulating—hormone receptor. Nature 371, 799–802.PubMedCrossRefGoogle Scholar
  33. 33.
    Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S., and Wolff, G. L. (1994) Obesity, diabetes, and neoplasia in yellow A(vy)/— mice: ectopic expression of the agouti gene. FASEB J. 8, 479–488.PubMedGoogle Scholar
  34. 34.
    Huszar, D., Lynch, C. A., Fairchild—Huntress, V., Dunmore, J. H., Fang, Q., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., Smith, F. J., Burn, P., and Lee, F. (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141.PubMedCrossRefGoogle Scholar
  35. 35.
    Zemel, M. B., Kim, J. H., Woychik, R. P., Michaud, E. J., Kadwell, S. H., and Patel, I. R. (1995) Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. Proc. Natl. Acad. Sci. U. S. A. 92, 4733–4737.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim, J. H., Kiefer, L. L., Woychik, R. P., Wilkison, W. O., Truesdale, A., Ittoop, O., Nichols, J., and Zemel, M. B. (1997) Agouti regulation of intracellular calcium: role of melanocortin receptors. Am. J. Physiol. 272, E379 - E384.PubMedGoogle Scholar
  37. 37.
    Willard, D. H., Bodnar, W., Harris, C., Kiefer, L., Nichols, J. S., Blanchard, S., Moyer, M., Burkhart, W., Weiel, J., and et al. (1995) Agouti structure and function: characterization of a potent alpha—melanocyte stimulating hormone receptor antagonist. Biochemistry 34, 12341–12346.PubMedCrossRefGoogle Scholar
  38. 38.
    Kiefer, L. L., Ittoop, O. R., Bunce, K., Truesdale, A. T., Willard, D. H., Nichols, J. S., Mountjoy, K., Chen, W. J., and Wilkison, W. O. (1997) Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors. Biochemistry 36, 2084–2090.PubMedCrossRefGoogle Scholar
  39. 39.
    Ying-Kui, Y., Ollmann, M. M., Wilson, B. D., Dickinson, C., Yamada, T., Barsh, G. S., and Gantz, I. (1997) Effects of recombinant agouti-signaling protein on melanocortin action. Mol. Endocrinol. 11, 274–280.CrossRefGoogle Scholar
  40. 40.
    Bultman, S. J., Michaud, E. J., and Woychik, R. P. (1992) Molecular characterization of the mouse agouti locus. Cell 71, 1195–1204.PubMedCrossRefGoogle Scholar
  41. 41.
    Wilson, B. D., Ollmann, M. M., Kang, L., Stoffel, M., Bell, G. I., and Barsh, G. S. (1995) Structure and function of ASP, the human homolog of the mouse agouti gene. Human Mol. Gene. 4, 223–230.CrossRefGoogle Scholar
  42. 42.
    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 up—regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602.PubMedCrossRefGoogle Scholar
  43. 43.
    Fong, T. M., Mao, C., MacNeil, T., Kalyani, R., Smith, T., Weinberg, D., Tota, M. R., and Van der Ploeg, L. H. T. (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
  44. 44.
    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, 135–138PubMedCrossRefGoogle Scholar
  45. 45.
    Graham, M., Shutter, 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
  46. 46.
    Schioth, H.B., Muceniece, R., Szardenings, M., Prusis, P., and Wikberg, J.E. (1996) Evidence indicating that the TM4, EL2, and TM5 of the melanocortin 3 receptor do not participate in ligand binding. Biochem. Biophys. Res. Commun. 229, 687–692.PubMedCrossRefGoogle Scholar
  47. 47.
    De Wildt, D. J., van der Ven, J. C., van Bergen, P., de Lang, H., and Versteeg, D. H. G. (1994) A hypotensive and bradycardic action of y2—melanocyte—stimulating hormone (y2—MSH) microinjected into the nucleus tractus solitarii of the rat. Arch. Pharmacol. 349, 50–56.CrossRefGoogle Scholar
  48. 48.
    Versteeg, D. H., Krugers, H., Meichow, C., De Lang, H., and de Wildt, D. J. (1993) Effect of ACTH—(4–10) and yz—MSH on blood pressure after intracerebroventricular and intracisternal administration. J. Cardiovasc. Pharmacol. 21, 907–911.PubMedCrossRefGoogle Scholar
  49. 49.
    Lin, S. Y., Wiedemann, E., and Humphreys, M. H. (1985) Role of the pituitary in reflex natriuresis following acute unilateral nephrectomy. Am. J. Physiol. 249, 390–395.Google Scholar
  50. 50.
    Ribstein, J. and Humphreys, M. H. (1984) Renal nerves and cation excretion after acute reduction in functioning renal mass in the rat. Am. J. Physiol. 246, F260 - F265.PubMedGoogle Scholar
  51. 51.
    Lin, S. Y., Chaves, C., Wiedemann, E., and Humphreys, M. H. (1987) A gammamelanocyte stimulating hormone—like peptide causes reflex natriuresis after acute unilateral nephrectomy. Hypertension 10, 619–627.PubMedCrossRefGoogle Scholar
  52. 52.
    Lymangrover, J. R., Buckalew, V. M., Harris, J., Klein, M. C., and Gruber, K. A. (1985) Gamma-2MSH is natriuretic in the rat. Endocrinology 116, 1227–1229.PubMedCrossRefGoogle Scholar
  53. 53.
    Ni, X. P., Kesterson, R. A., Sharma, S. D., Hruby, V. J., Cone, R. D., Wiedemann, E., and Humphreys, M. H. (1997) Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists. (1998) Am. J. Physiol. 274, R931 - R938.Google Scholar
  54. 54.
    Pedersen, R. C. and Brownie, A. C. (1983) Lys—gamma 3—melanotropin binds with high affinity to the rat adrenal cortex. Endocrinology 112, 1279–1287.PubMedCrossRefGoogle Scholar
  55. 55.
    Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G., and Gruters, A. (1998) Severe early—onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157.PubMedCrossRefGoogle Scholar
  56. 56.
    Yang, Y. K., Ollmann, M. M. M., Wilson, B. D., et al. (1997) Effects of recombinant agouti-signaling protein on melanocortin action. Molec. Endocrinol. 11, 274–280.CrossRefGoogle Scholar
  57. 57.
    Schioth, H. B., Muceniece, R., Wikberg, J. E., and Chhajlani, V. (1995) Characterization of melanocortin receptor subtypes by radioligand binding analysis. Eur. J. Pharmacol. 288, 311–317.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Robert A. Kesterson

There are no affiliations available

Personalised recommendations