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Currents | Issue 5 • Winter 1997

Printable Version

Eicosanoid Receptors

The Classical Receptors

by Kirk M. Maxey, M.D.

The study of transmembrane, G-protein-coupled eicosanoid receptors is a mature field. All types and subtypes of the prostanoid receptors (FP, EP, TP, DP, and IP) have been cloned from a minimum of human and murine sources. In addition, several have been cloned from rat, bovine and rabbit libraries. The field is rich in new findings from pharmacologic experiments. Second messenger studies have revealed activation pathways for each occupied receptor which provide access to the signal transduction machinery of the cell. The presence of several different splice variants of some receptors (such as the 6 variations of the EP3 receptor) hints strongly at differences in tissue responsiveness based on tissue-specific receptor subtype distribution. The tools for expanding this field are becoming available in the form of specific and selective antibodies for each receptor. New and more selective agonists and antagonists are also being developed. Finally, each receptor gene that is isolated allows the logical next step of generating knockout animal models lacking full expression of the receptor protein. This can help to further define the developmental and physiologic functions of the receptors in intact animals.

Less than ten years have elapsed since the cloning of the first eicosanoid receptor, so the accumulation of this knowledge represents a considerable achievement. We at Cayman would like to acknowledge all of those who have contributed to this work by developing a graphic representation to summarize what has been accomplished. Included in this special issue of Currents is an illustration showing the sequence and the distinguishing pharmacologic properties of each of the major eicosanoid receptor subtypes. Distribution of the receptors in various tissues is a general ranking from most to least abundant. It should be noted that this order often varies between species and between different publications. In most cases, the abundance information is the data from Northern blot analysis. The rank order of ligand binding affinity listed in the table reflects data from functional assays as well as from displacement data using recombinant proteins. An attempt has been made to include the most potent and specific agonists and antagonists, with the necessary exclusion of some well studied molecules with nonselective affinities for several receptors.

The graphical representations of the receptors reflect data from mouse and human cloning experiments. Homologies between receptor subtypes and between species have been indicated as faithfully as possible. Glycosylation sites are in many cases putative residues which may not bear oligosaccharides in the native receptor. We hope that this summary will serve as a useful tool to further the research endeavors of all who work in the eicosanoid field.

The first reports of eicosanoids acting via nuclear receptors appeared about 18 months ago in a pair of papers in Cell.1,2 These authors reported that 15-deoxy-Δ12,14-PGJ2 was a ligand for the PPARγ nuclear receptor. Activation of the PPARγ receptor results in adipogenesis, whereby fibroblasts differentiate into adipocytes through the transcriptional activation of more than a dozen quiescent genes. Then in November of 1996, a third paper by Walter Wahli, Frank Gonzalez and their coworkers appeared.3 They reported that Leukotriene B4 (LTB4) is a ligand for the related PPARα nuclear receptor. In this case, receptor stimulation leads to the increased expression of Acyl-CoA oxidase and other enzymes associated with increased β- and ω-oxidation of lipids and fatty acids.

The authors proposed that this accelerates inactivation of LTB4 by its normal metabolic pathway, leading to a negative feedback control of the inflammatory process. (See illustration)

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References

  1. Boie, Y, et al. J. Biol. Chem. 270, 18916 (1995).
  2. Hirata, M., et al. Proc. Natl. Acad. Sci. USA 91, 11192-11196 (1994).
  3. Ito, S., et al. Adv. Prostaglandin Thromboxane Leukotriene Res. 21, 371-374 (1990).
  4. Schafer, A.I., et al. J. Biol. Chem. 254, 2914-2917 (1979).
  5. Town, M-H., et al. Prostaglandins 25, 13-28 (1983).
  6. Thierauch, K.H., et al. Prostaglandins 35, 855-868 (1988).
  7. Bundy, G.L., et al. J. Med. Chem. 26, 790-799 (1983).
  8. Giles, H., et al. Br. J. Pharmacol. 96, 291-300 (1989).
  9. Virgolini, I., et al. J. Biol. Chem. 267, 12700-12708 (1992).
  10. Crankshaw, D.J. and Gaspar, V. J. Reprod. Fertil. 103, 55-61 (1995).
  11. Alvarez, R., et al. Prostaglandins 42, 105-119 (1991).
  12. Coleman, R.A., et al. Pharmacol. Rev. 46, 205-229 (1994).
  13. Matsumura, H., et al. Proc. Natl. Acad. Sci. USA 91, 11998-12002 (1994).
  14. Onoe, H., et al. Proc. Natl. Acad. Sci. USA 85, 4082-4086 (1988).
  15. Narumiya, S. and Toda, N. Br. J. Pharmacol. 85, 367-375 (1985).
  16. Siegl, A.M. Methods Enzymol. 86, 179-192 (1982).
  17. Funk, C.D., et al. J. Biol. Chem. 268, 26767-26772 (1993).
  18. Watabe, A., et al. J. Biol. Chem. 268, 20175-20178 (1993).
  19. Miller, W.L., et al. Prostaglandins 9, 9-18 (1975).
  20. Lawrence, R.A., et al. Br. J. Pharmacol. 105, 271-278 (1992).
  21. Kennedy, I., et al. Adv. Prostaglandin Thromboxane Leukotriene Res. 11, 327-332 (1983).
  22. Woodward, D.F., et al. Biochem. Pharmacol. 50, 1731-1733 (1995).
  23. Regan, J.W., et al. Mol. Pharmacol. 46, 213-220 (1994).
  24. Talpain, E., et al. Br. J. Pharmacol. 114, 1459-1465 (1995).
  25. De Vries, G.W., et al. Br. J. Pharmacol. 115, 1231-1234 (1995).
  26. Woodward, D.F., et al. Prostaglandins 46, 371-383 (1993).
  27. Adam, M., et al. FEBS Lett. 338, 170-174 (1994).
  28. Kunapuli, S.P., et al. Biochem. J. 298, 263-267 (1994).
  29. Yang, J., et al. Biochem. Biophys. Res. Commun. 198, 999-1006 (1994).
  30. Kotani, M., et al. Mol. Pharmacol. 48, 869-879 (1995).
  31. Schmid, A., et al. Eur. J. Biochem. 228, 23-30 (1995).
  32. Sugimoto, Y., et al. J. Biol. Chem. 267, 6463-6466 (1992).
  33. Sugimoto, Y., et al. J. Biol. Chem. 268, 2712-2718 (1993).
  34. Irie, A., et al. Eur. J. Biochem. 217, 313-318 (1993).
  35. Namba, T., et al. Nature 365, 166-170 (1993).
  36. Takeuchi, K., et al. Biochem. Biophys. Res. Commun. 199, 834-840 (1994).
  37. Takeuchi, K., et al. Biochem. Biophys. Res. Commun. 194, 885-891 (1993).
  38. Breyer, R.M., et al. J. Biol. Chem. 269, 6163-6169 (1994).
  39. Bunce, K.T., et al. Adv. Prostaglandin Thromboxane Leukotriene Res. 21, 379-382 (1990).
  40. Collins, P.W. et al. Medicinal Research Reviews 10, 149-172 (1990).
  41. Negishi, M., et al. Prostaglandins 48, 275-283 (1994).
  42. Strong, P., et al. Prostaglandins 43, 559-566 (1992).
  43. Lawrence, R.A. and Jones, R.L. Br. J. Pharmacol. 105, 817-824 (1992).
  44. Bastien, L., et al. J. Biol. Chem. 269, 11873-11877 (1994).
  45. An, S., et al. Biochem. Biophys. Res. Commun. 197, 263-270 (1993).
  46. Sando, T., et al. Biochem. Biophys. Res. Commun. 200, 1329-1333 (1994).
  47. Breyer, R.M., et al. Am. J. Physiol. 270, F485-F493 (1996).
  48. Honda, A., et al. J. Biol. Chem. 268, 7759-7762 (1993).
  49. Nishigaki, N., et al. FEBS Lett. 364, 339-341 (1995).
  50. Mori, K., et al. J. Mol. Med. 74, 333-336 (1996).
  51. Smith, G.C.S., et al. J. Pharmacol. Exp. Ther. 271, 390-396 (1994).
  52. Coleman, R.A., et al. Prostaglandins 47, 151-168 (1994).
  53. Abramovitz, M., et al. J. Biol. Chem. 269, 2632-2636 (1994).
  54. Sugimoto, Y., et al. J. Biol. Chem. 269, 1356-1360 (1994).
  55. Sakamoto, K., et al. J. Biol. Chem. 269, 3881-3886 (1994).
  56. Carrasco, M.P., et al. J. Clin. Endocrinol. Metab. 81, 2104-2110 (1996).
  57. Raymond, V., et al. Biochem. Biophys. Res. Commun. 116, 39-46 (1983).
  58. Kimball, F.A. and Wyngarden, L.J. Prostaglandins 13, 553-564 (1977).
  59. Dukes, M., et al. Nature 250, 330-331 (1974).
  60. Woodward, D.F., et al. Adv. Prostaglandin Thromboxane Leukotriene Res. 21, 367-370 (1990).
  61. Maddox, Y.T., et al. Nature 273, 549-552 (1978).
  62. Nakagawa, O., et al. Circulation 90, 1643-1647 (1994).
  63. Boie, Y., et al. J. Biol. Chem. 269, 12173-12178 (1994).
  64. Katsuyama, M., et al. FEBS Lett. 344, 74-78 (1994).
  65. Namba, T., et al. J. Biol. Chem. 269, 9986-9992 (1994).
  66. Sasaki, Y et al. Biochim. Biophys. Acta 1224, 601-605 (1994).
  67. Oliva, D. and Nicosia, S. Pharmacol. Res. Commun. 19, 735-765 (1987).
  68. Whittle, B.J.R., et al. Prostaglandins 19, 605-627 (1980).
  69. Morita, A., et al. Life Sci. 27, 695-701 (1980).
  70. Aiken, J.W. and Shebuski, R.J. Prostaglandins 19, 629-643 (1980).
  71. Kobzar, G., et al. J. Lipid Mediators Cell Signalling 10, 2443-249 (1994).
  72. St¤rzebecher, S., et al. Prostaglandins 31, 95-109 (1986).
  73. Merritt, J.E., et al. Br. J. Pharmacol. 102, 260-266 (1991).
  74. Merritt, J.E., et al. Br. J. Pharmacol. 102, 251-259 (1991).
  75. SchrÜr, K., et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 252-255 (1981).
  76. Armstrong, R.A., et al. Br. J. Pharmacol. 97, 657-668 (1989).
  77. Raychowdhury, M.K., et al. J. Biol. Chem. 269, 19256-19261 (1994).
  78. Hirata, M., et al. Nature 349, 617-620 (1991).
  79. Namba, T., et al. Biochem. Biophys. Res. Commun. 184, 1197-1203 (1992).
  80. D'Angelo, D.D., et al. J. Pharmacol. Exp. Ther. 271, 1034-1041 (1994).
  81. Morinelli, T.A., et al. Adv. Prostaglandin Thromboxane Leukotriene Res. 20, 102-109 (1990).
  82. Lefer, A.M., et al. Proc. Natl. Acad. Sci. USA 77, 1706-1710 (1980).
  83. Coleman, R.A., et al. Br. J. Pharmacol. 73, 773-778 (1981).
  84. Tymkewycz, P.M., et al. Br. J. Pharmacol. 102, 607-614 (1991).
  85. Grover, G.J. and Schumacher, W.A. Basic Res. Cardiol. 84, 103-110 (1989).
  86. Hedberg, A., et al. J. Pharmacol. Exp. Ther. 245, 786-792 (1988).
  87. Lumley, P., et al. Br. J. Pharmacol. 97, 783-794 (1989).
  88. Brittain, R.T., et al. Circulation 72, 1208-1218 (1985).
  89. Kishino, J., et al. Br. J. Pharmacol. 103, 1883-1888 (1991).
  90. Bertolino, F., et al. Br. J. Pharmacol. 115, 210-216 (1995).
  91. Krauss, A.H.-P., et al. J. Ocul. Pharmacol. Ther. 11, 203-212 (1995).
  92. Saussy, Jr., et al. Mol. Pharmacol. 39, 72-78 (1991).
  93. Coleman, R.A. and Sheldrick, R.L.G. Br. J. Pharmacol. 96, 688-692 (1989).

Nuclear Eicosanoid Receptors—New Developments

  1. Kliewer, S.A., Lenhard, J.M., Willson, T.M. et al. Cell 83, 813-819 (1995).
  2. Forman, B.M., Tontonoz, P., Chen, J. et al. Cell 83, 803-812 (1995).
  3. Devchand, P.R., Keller, H., Peters, J.M. et al. Nature 384, 39-43 (1996).
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