Regulation of Inositol Trisphosphate Formation and Action

  • James W. PutneyJr.
Part of the New Horizons in Therapeutics book series (NHTH)


Over 30 years have now passed since the original report by Hokin and Hokin on receptor-stimulated turnover of inositol lipids (Hokin and Hokin, 1953). Since that time, the phosphoinositides have enjoyed periods of interest, neglect, rekindled interest, controversy, and finally acceptance as important intermediaries in biological signaling processes in a wide variety of systems. The pivotal contributions that resulted in this tumultuous history came from a number of different laboratories. Michell’s (1975) hypothesis that the phosphoinositides somehow served to couple receptors to cellular calcium mobilization provoked considerable research and criticism, but it was ultimately shown to be correct when Berridge, Irvine, and their collaborators demonstrated that inositol 1,4,5-trisphosphate [(1,4,5)IP3], the water-soluble product of phospholipase C degradation of phosphatidylinositol 4,5-bisphosphate (PIP2), was capable of releasing sequestered calcium intracellularly in a variety of biological systems (Berridge 1983, 1984; Berridge and Irvine, 1984; Streb et al., 1983; Burgess et al., 1984a,b; Prentki et al., 1984). A parallel story evolved from the work in Nishizuka’s laboratory (Nishizuka, 1983, 1984), which demonstrated that the other product of inositol lipid breakdown, diacylglycerol (DG) was also a cellular messenger; this apparently innocuous intermediate of phospholipid metabolism was shown to be a potent and specific activator of an ubiquitous protein kinase that Nishizuka designated as C kinase.


Adenylate Cyclase Calcium Release Guanine Nucleotide Pertussis Toxin Calcium Entry 


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  1. Aub, D. L., McKinney, J. S., and Putney, J. W., Jr., 1982, Nature of the receptor-regulated calcium pool in the rat parotid gland, J. Physiol. (Lond.) 331: 557–565.Google Scholar
  2. Baker, P. F., and Knight, D. E., 1978, Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes, Nature 276: 620–622.PubMedCrossRefGoogle Scholar
  3. Batty, I. R., Nahorski, S. R., and Irvine, R. F., 1985, Rapid formation of inositol 1,3,4,5tetrakisphosphate following muscarinic receptor stimulation of rat cerebral cortical slices. Biochem. J. 232: 211–215.PubMedGoogle Scholar
  4. Berridge, M. J., 1983, Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyze polyphosphoinositides instead of phosphatidylinositol, Biochem J. 212: 849–858.PubMedGoogle Scholar
  5. Berridge, M. J., 1984, Inositol trisphosphate and diaclyglycerol as second messengers, Biochem. J. 220: 345–360.PubMedGoogle Scholar
  6. Berridge, M. J., and Fain, J. N., 1979, Inhibition of phosphatidylinositol synthesis and the inactivation of calcium entry after prolonged exposure of the blowfly salivary gland to 5-hydroxytryptamine, Biochem. J. 178: 59–69.PubMedGoogle Scholar
  7. Berridge, M. J., and Irvine, R. F., 1984, Inositol trisphosphate, a novel second messenger in cellular signal transduction, Nature 312: 315–321.PubMedCrossRefGoogle Scholar
  8. Burgess, G. M., McKinney, J. S., Fabiato, A., Leslie, B. A., and Putney, J. W., Jr., 1983, Calcium pools in saponin-permeabilized guinea-pig hepatocytes, J. Biol. Chem. 258: 15336–15345.PubMedGoogle Scholar
  9. Burgess, G. M., Godfrey, P. P., McKinney, J. S., Berridge, M. J., Irvine, R. F., and Putney, J. W., Jr., 1984a, The second messenger linking receptor activation to internal Ca release in liver, Nature 309: 63–66.PubMedCrossRefGoogle Scholar
  10. Burgess, G. M., Irvine, R. F., Berridge, M. J., McKinney, J. S., and Putney, J. W., Jr., 1984b, Actions of inositol phosphates on Ca pools in guinea-pig hepatocytes, Biochem.J. 224: 741–746.PubMedGoogle Scholar
  11. Burgess, G. M., McKinney, J. S., Irvine, R. F., and Putney, J. W., Jr., 1985, Inositol 1,4,5trisphosphate and inositol 1,3,4-trisphosphate formation in Ca2+-mobilizing hormone-activated cells, Biochem. J. 232: 237–243.PubMedGoogle Scholar
  12. Cockcroft, S., 1981, Does phosphatidylinositol breakdown control the Cat+-gating mechanism?, Trends Pharmacol. Sci. 2: 340–342.CrossRefGoogle Scholar
  13. Cockcroft, S., and Gomperts, B. D., 1985, Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase, Nature 314: 534–536.PubMedCrossRefGoogle Scholar
  14. Delfert, D. M., Hill, S., Pershadsingh, H. H., Sherman, W. R., and McDonald, J. M., 1986, myo-Inositol 1,4,5-trisphosphate mobilizes Caz+ from endoplasmic reticulum but not from plasma membrances, Biochem J. 236: 37–44.Google Scholar
  15. El-Refai, M. F., Blackmore, P. F., and Exton, J. H., 1979, Evidence for two a-adrenergic binding sites in liver plasma membranes. Studies with [3H]epinephrine and [3H]dihydroergocryptine, J. Biol. Chem. 254: 4375–4386.PubMedGoogle Scholar
  16. Evans, T., Martin, M. W., Hughes, A. R., and Harden, T. K., 1985, Guanine nucleotide-sensitive, high affinity binding of carbachol to muscarinic cholinergic receptors of 1321N1 astrocytoma cells is insensitive to pertussis toxin, Mol. Pharmacol. 27: 32–37.PubMedGoogle Scholar
  17. Exton, J. H., 1980, Mechanisms involved in a-adrenergic phenomena: Role of calcium ions in actions of catecholamines in liver and other tissues, Am. J. Physiol. 238: E3–E12.PubMedGoogle Scholar
  18. Gonzales, R. A., and Crews, F. T., 1985, Guanine nucleotides stimulate production of inositol trisphosphate in rat cortical membranes, Biochem. J. 232: 799–804.PubMedGoogle Scholar
  19. Goodhardt, M., Ferry, N., Geynet, P., and Hanoune, J., 1982, Hepatic a-adrenergic receptors show agonist-specific regulation by guanine nucleotides. Loss of nucleotide effect after adrenalectomy, J. Biol. Chem. 257: 11577–11583.PubMedGoogle Scholar
  20. Haslam, R. J., and Davidson, M. M. L., 1984a, Potentiation by thrombin of the secretion of serotinin from permeabilized platelets equilibrated with Cat+ buffers. Relationship to protein phosphorylation and diacylglycerol formation, Biochem. J. 222: 351–361.PubMedGoogle Scholar
  21. Haslam, R. J., and Davidson, M. M. L., 1984b, Receptor-induced diacylglycerol formation in permeabilized platelets; possible role for a GTP-binding protein, J. Receptor Res. 4: 605–629.Google Scholar
  22. Hokin, M. R., and Hokin, L. E., 1953, Enzyme secretion and the incorporation of P into phospholipides of pancreas slices, J. Biol. Chem. 203: 967–977.PubMedGoogle Scholar
  23. Irvine, R. F., and Moor, R. M., 1986, Micro-injection of inositol 1,3,4,5-tetrakisphosphate activates sea urchin eggs by a mechanism dependent on external Cat+, Biochem. J. 240: 917–920.PubMedGoogle Scholar
  24. Irvine, R. F., Letcher, A. J., Lander, D. J., and Downes, C. P., 1984, Inositol trisphosphates in carbachol-stimulated rat parotid glands, Biochem. J. 223: 237–243.PubMedGoogle Scholar
  25. Irvine, R. F., Letcher, A. J., Heslop, J. P., and Berridge, M. J., 1986a, The inositol tris/ tetrakisphosphate pathway-Demonstration of Ins(1,4,5)P3 3-kinase activity in animal tissues, Nature 320: 631–634.PubMedCrossRefGoogle Scholar
  26. Irvine, R. F., Letcher, A. J., Lander, D. J., and Berridge, M. J., 1986b, Specificity of inositol phosphate-stimulated Ca2+ mobilization from Swiss-mouse 3T3 cells, Biochem J. 240: 301–304.PubMedGoogle Scholar
  27. Joseph, S. K., Thomas, A. P., Williams, R. J., Irvine, R. F., and Williamson, J. R., 1984, mvo-Inositol 1,4,5-trisphosphate, a second messenger for the hormonal mobilization of intracellular Ca2+ in the liver, J. Biol. Chem. 259: 3077–3081.Google Scholar
  28. Leeb-Lundberg, L. M.. Cotecchia, S., Lomasney, J. W., DeBernardis, J. F., Lefkowitz, R. J., and Caron, M. G.. 1985, Phorbol esters promote ct-adrenergic receptor phosphorylation and receptor uncoupling from inositol phospholipid metabolism, Proc. Natl. Acad. Sci. U.S.A. 82: 5651–5655.Google Scholar
  29. Litosch, I., and Fain, J. N., 1985, 5-Methyltryptamine stimulates phospholipase C-mediated breakdown of exogenous phosphoinositides by blowfly salivary gland membranes, J. Biol. Chem. 260: 16052–16055.Google Scholar
  30. Litosch, I.. and Fain. J. N., 1986, Regulation of phosphoinositide breakdown by guanine nucleotides. Life Sci. 39: 187–194.PubMedCrossRefGoogle Scholar
  31. Litosch, I., Wallis. C.. and Fain. J. N., 1985. 5-Hydroxytryptamine stimulates inositol phosphate production in a cell-free system from blowfly salivary glands. Evidence for a role of GTP in coupling receptor activation to phosphoinositide breakdown, J. Biol. Chem. 260: 5464–5471.Google Scholar
  32. Lucas. D. O.. Bajjalieh, S. M., Kowalchyk, J. A., and Martin, T. F. J., 1985, Direct stimulation by thyrotropin-releasing hormone (TRH) of polyphosphoinositide hydrolysis in GH cell membranes by a guanine nucleotide-modulated mechanism, Biochem. Biophys. Res. Commun. 132: 721–728.Google Scholar
  33. Lynch, C. J., Charest, R. Bocckino, S. B., Exton, J. H., and Blackmore, P. F., 1985, Inhibition of hepatic a1-adrenergic effects and binding by phorbol myristate acetate, J. Biol. Chem. 260: 2844–2851.PubMedGoogle Scholar
  34. Merritt, J. E., Taylor, C. W., Rubin, R. P., and Putney. J. W., Jr., 1986, Evidence suggesting that a novel G-protein couples receptors to phospholipase C in exocrine pancreas, Biochem. J. 236: 337–343.PubMedGoogle Scholar
  35. Michell, R. H., 1975, Inositol phospholipids and cell surface receptor function, Biochim. Biophys. Acta 415: 81–147.PubMedGoogle Scholar
  36. Nambi, P., Stadel, J. M., Sibley, D. R., Strulovici, B., Caron, M. G., and Lefkowitz, R. J., 1985, Mechanisms of ß-adrenergic receptor desensitization, Sven. Med. Hoechst 19: 437–451.Google Scholar
  37. Nishizuka, Y., 1983. Calcium, phospholipid turnover and transmembrane signalling, Philos. Trans. R. Soc. Lond.(Biol.) 302: 101–112.CrossRefGoogle Scholar
  38. Nishizuka, Y., 1984, Turnover of inositol phospholipids and signal transduction, Science 225: 1365–1370.PubMedCrossRefGoogle Scholar
  39. Prentki, M., Biden, T. J., Janjic, D., Irvine, R. F.. Berridge, M. J., and Wollheim, C. B., 1984, Rapid mobilization of Cat-f-from rat insulinoma microsomes by inositol 1.4,5trisphosphate, Nature 309: 562–564.PubMedCrossRefGoogle Scholar
  40. Putney, J. W., Jr., 1986, A model for receptor-regulated calcium entry, Cell Calcium, 7: 1–12.PubMedCrossRefGoogle Scholar
  41. Putney, J. W., Jr., 1987, Formation and actions of the calcium mobilizing messenger, inositol 1,4,5-trisphosphate, Am. J. Physiol. (Gastrointest. Liver Physiol.) 252: G149–G157.Google Scholar
  42. Putney, J. W., Jr., Poggioli, J., and Weiss, S. J., 1981, Receptor regulation of calcium release and calcium permeability in parotid gland cells, Philos. Trans. R. Soc. Lond. Biol. 296: 37–45.PubMedCrossRefGoogle Scholar
  43. Rodbell, M., 1980, The role of hormone receptors and GTP-regulatory proteins in membrane transduction, Nature 284: 17–22.PubMedCrossRefGoogle Scholar
  44. Slack, B. E., Bell, J. E., and Benos, D. J., 1986, Inositol 1,4,5-trisphosphate injection mimics fertilization potentials in sea urchin eggs, Am. J. Physiol. (Cell Physiol.) 250: C340–C344.Google Scholar
  45. Smigel, M., Katada, T., Northup, J. K.. Bokoch, G. M., Ui, M., and Gilman, A. G., 1984, Mechanisms of guanine nucleotide-mediated regulation of adenylate cyclase activity, Adv. Cyclic Nucleotide Protein Phosphorvlation Res. 17: 1–18.Google Scholar
  46. Smith, C. D., Cox, C. C., and Snyderman, R., 1986, Receptor-coupled activation of phosphoinositide-specific phospholipase C by an N protein, Science 232: 97–100.Google Scholar
  47. Snavely, M. D., and Insel, P. A., 1982, Characterization of a-adrenergic receptor subtypes in the rat renal cortex. Differential regulation of al-and a2-adrenergic receptors by guanyl nucleotides and Nat, Mol. Pharmacol. 22: 532–546.PubMedGoogle Scholar
  48. Spat, A., Bradford, P. G., McKinney, J. S., Rubin, R. P., and Putney, J. W., Jr., 1986a, A saturable receptor for [32P]inositol-(1,4,5)trisphosphate in guinea pig hepatocytes and rabbit neutrophils, Nature 319: 514–516.PubMedCrossRefGoogle Scholar
  49. Spat, A., Fabiato, A., and Rubin, R. P., 1986b, Binding of inositol trisphosphate by a liver microsomal fraction, Biochem. J. 233: 929–932.PubMedGoogle Scholar
  50. Streb, H., Irvine, R. F., Berridge, M. J., and Schulz, I., 1983, Release of Ca2± from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate, Nature 306: 67–68.PubMedCrossRefGoogle Scholar
  51. Sugiya, H., Tennes, K. A., and Putney, J. W., Jr., 1987, Homologous desensitization of substance P-induced inositol polyphosphate formation in rat parotid acinar cells, Biochem. J. 244: 647–653.PubMedGoogle Scholar
  52. Taylor, C. W., and Merritt, J. E., 1986, Receptor coupling to polyphosphoinositide turnover: A parallel with the adenylate cyclase system, Trends Pharmacol. Sci. 7: 238–242.CrossRefGoogle Scholar
  53. Taylor, C. W., and Putney, J. W., Jr., 1985, Size of the inositol 1,4,5-trisphosphate-sensitive calcium pool in guinea-pig hepatocytes, Biochem. J. 232: 435–438.PubMedGoogle Scholar
  54. Taylor, C. W., Merritt, J. E., Putney, J. W., Jr., and Rubin, R. P., 1986a, A guanine nucleotide-dependent regulatory protein couples substance P receptors to phospholipase C in rat parotid gland, Biochem. Biophys. Res. Commun. 136: 362–368.PubMedCrossRefGoogle Scholar
  55. Taylor, C. W., Merritt, J. E., Putney, J. W., Jr., and Rubin, R. P., 1986b, Effects of Ca2+ on phosphoinositide breakdown in exocrine pancreas, Biochem. J. 238: 765–772.PubMedGoogle Scholar
  56. Tennes, K. A., McKinney, J. S., and Putney, J. W., Jr., 1987, Metabolism of inositol 1,4,5-trisphosphate in guinea pig hepatocytes, Biochem. J. 242: 797–802.PubMedGoogle Scholar
  57. Ueda, T., Church, S. H., Noel, M. W., and Gill, D. L., 1986, Influence of inositol 1,4,5trisphosphate and guanine nucleotides on intracellular calcium release within the N1E-115 neuronal cell line, J. Biol. Chem. 261: 3184–3192.PubMedGoogle Scholar
  58. Uhing, R. J., Jiang, H., Prpic, V., and Exton, J. H., 1985, Regulation of a liver plasma membrane phosphoinositide phosphodiesterase by guanine nucleotides and calcium, FEBS Lett. 188: 317–320.PubMedCrossRefGoogle Scholar
  59. Uhing, R. J., Prpic, V., Jiang, H., and Exton, J. H., 1986, Hormone-stimulated polyphosphoinositide breakdown in rat liver plasma membranes, J. Biol. Chem. 261: 2140–2146.PubMedGoogle Scholar
  60. Ui, M., 1986, Pertussis toxin as a probe of receptor coupling to inositol lipid metabolism, in: Phosphoinositides and Receptor Mechanisms ( J. W. Putney, Jr., ed.) pp. 163–195, Alan R. Liss, New York.Google Scholar
  61. Vincenti, L. M., Di Virgilio, F., Ambrosini, A., Pozzan, T, and Meldolesi, J., 1985, Tumor promoter phorbol 12-myristate, 13-acetate inhibits phosphoinositide hydrolysis and cytosolic Ca2+ rise induced by the activation of muscarinic receptors in PC12 cells, Biochem. Biophys. Res. Commun. 127: 310–317.CrossRefGoogle Scholar
  62. Watson, S. P., and Lapetina, E. G., 1985, 1,2-Diacylglycerol and phorbol ester inhibit agonist-induced formation of inositol phosphates in human platelets: Possible implications for negative feedback regulation of inositol phospholipid hydrolysis, Proc. Natl. Acad. Sci. U.S.A. 82: 2623–2626.Google Scholar
  63. Williamson, J. R., Cooper, R. H., and Hoek, J. B., 1981, Role of calcium in the hormonal regulation of liver metabolism, Biochim. Biophys. Acta 639: 243–295.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • James W. PutneyJr.
    • 1
  1. 1.Section of Calcium Regulation, Laboratory of PharmacologyNational Institute of Environmental Health SciencesResearch Triangle ParkUSA

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