Skip to main content
SpringerLink
Log in
Book cover

The Melanocortin Receptors pp 385–403Cite as

The Melanocortin-3 Receptor

  • Chapter

  • 147 Accesses

Part of the book series: The Receptors ((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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  10. Biervert, C., Schroeder, B. C., Kubisch, C., et al. (1998) A potassium channel mutation in neonatal human epilepsy. Science 279, 403–406.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  21. Xia, Y. and Wikberg, J. E. S. (1997) Postnatal expression of melanocortin-3 receptor in rat diencephalon and mesencephalon. Neuropharmacology 36, 217–224.

    Article  PubMed  CAS  Google Scholar 

  22. Chhajlani, V. (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem. Mole. Biol. Int. 38, 73–80.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  40. Bultman, S. J., Michaud, E. J., and Woychik, R. P. (1992) Molecular characterization of the mouse agouti locus. Cell 71, 1195–1204.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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, 135–138

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Robert A. Kesterson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Vollum Institute, Oregon Health Sciences University, Portland, OR, USA

    Roger D. Cone

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer Science+Business Media New York

About this chapter

Cite this chapter

Kesterson, R.A. (2000). The Melanocortin-3 Receptor. In: Cone, R.D. (eds) The Melanocortin Receptors. The Receptors. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-031-5_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-031-5_13

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-082-3

  • Online ISBN: 978-1-59259-031-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation