Inositol Phosphate Metabolism and Cellular Signal Transduction

  • James W. PutneyJr.
  • Arlene R. Hughes
  • Debra A. Horstman
  • Haruo Takemura
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 255)


Over thirty years have now past since the original report by Hokin and Hokin of receptor-stimulated turnover of inositol lipids1. Today, the impact of this phenomenon on a multitude of important biological systems is widely appreciated. Since the first papers by the Hokins, the phosphoinositides have enjoyed periods of interest, neglect, controversy and finally acceptance as important precursors for biological signals in a variety of systems. The important contributions which lead to our current understanding of this system came from a number of different laboratories. Micheli’s2 hypothesis that the phosphoinositides somehow served to couple receptors to cellular calcium mobilization provoked considerable research and criticism. Progress in understanding the exact role of inositol lipid turnover in receptor mechanisms was hindered by lack of knowledge of the biochemical pathways involved. By the early 1980’s the experimental evidence began to indicate that the initial reaction in stimulated phosphoinositide turnover was the breakdown of not the major known inositide, phosphatidyl inositol, but rather a minor phosphorylated derivative, phosphatidylinositol 4,5-bisphosphate3,4. Berridge5 suggested that the water soluble product of this reaction, inositol 1,4,5-trisphosphate [(1,4,5)IP3], might act as a second messenger to activate the release of Ca2+ from intracellular stores.


Calcium Entry Inositol Phosphate Inositol Trisphosphate Muscarinic Receptor Antagonist AR42J Cell 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hokin, M.R., and L.E. Hokin, Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices, J. Biol. Chem. 203:967 (1953).PubMedGoogle Scholar
  2. 2.
    Micheli, R.H., Inositol phospholipids and cell surface receptor function, Biochim. Biophys. Acta 415:81 (1975).Google Scholar
  3. 3.
    Abdel-Latif, A.A., R. Akhtar, and J.N. Hawthorne, Acetylcholine increases the breakdown of triphosphoinositide of rabbit iris muscle prelabelled with [32P]phosphate, Biochem. J. 162:61 (1977).PubMedGoogle Scholar
  4. 4.
    Kirk, C.J., J.A. Creba, C.P. Downes, and R.H. Micheli, Hormone-stimulated metabolism of inositol lipids and its relationship to hepatic receptor function, Biochem. Soc. Trans. 9:377 (1981).PubMedGoogle Scholar
  5. 5.
    Berridge, M.J., Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphat-idylinositol, Biochem. J. 212:849 (1983).PubMedGoogle Scholar
  6. 6.
    Streb, H., R.F. Irvine, M.J. Berridge, and I. Schulz, Release of Ca2+ from a nonmitochondrial store in pancreatic cells by inositol-l,4,5-trisphosphate, Nature 306:67 (1983).PubMedCrossRefGoogle Scholar
  7. 7.
    Berridge, M.J., Inositol phosphates as second messengers, in: Phosphoinositides and Receptor Mechanisms, Putney, J.W., Jr., ed., p. 25–46, Alan R. Liss, Inc., New York (1986).Google Scholar
  8. 8.
    Berridge, M.J., R.M. Dawson, C.P. Downes, J.P. Heslop, and R.F. Irvine, Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides, Biochem. J. 212:473 (1983).PubMedGoogle Scholar
  9. 9.
    Majerus, P.W., T.M. Connolly, V.S. Bansal, R.C. Inhorn, T.S. Ross, and D.L. Lips, Inositol phosphates: Synthesis and degradation, J. Biol. Chem. 263:3051 (1988).PubMedGoogle Scholar
  10. 10.
    Putney, J.W., Jr., Calcium-mobilizing receptors, Trends Pharmacol. Sci. 8:481 (1987).CrossRefGoogle Scholar
  11. 11.
    Downes, C.P., M.C. Mussat, and R.H. Micheli, The inositol trisphos-phate Phosphomonoesterase of the human erythrocyte membrane, Biochem. J. 203:169 (1982).PubMedGoogle Scholar
  12. 12.
    Inhorn, R.C., V.S. Bansal, and P.W. Majerus, Pathway for 1,3,4-tris-phosphate and 1,4-bisphosphate metabolism, Proc. Nat. Acad. Sci. USA 84:2170 (1987).PubMedCrossRefGoogle Scholar
  13. 13.
    Irvine, R.F., A.J. Letcher, J.P. Heslop, and M.J. Berridge, The inositol tris/tetrakisphosphate pathway — demonstration of Ins(l,4,5)P3 3-kinase activity in animal tissues, Nature 320:631 (1986).PubMedCrossRefGoogle Scholar
  14. 14.
    Bansal, V.S., R.C. Inhorn, and P.W. Majerus, The metabolism of inositol 1,3,4-trisphosphate to inositol 1,3-bisphosphate, J. Biol. Chem. 262:9444 (1987).PubMedGoogle Scholar
  15. 15.
    Irvine, R.F., and R.M. Moor, Micro-injection of inositol 1,3,4,5-tet-rakisphosphate activates sea urchin eggs by a mechanism dependent on external Ca2+, Biochem. J. 240:917 (1986).PubMedGoogle Scholar
  16. 16.
    Morris, A.P., D.V. Gallacher, R.F. Irvine, and O.H. Petersen, Synergism of inositol trisphosphate and tetrakisphosphate in activating Ca2+-dependent K+ channels, Nature 330:653 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    Horstman, D.A., H. Takemura, and J.W. Putney, Jr., Formation and metabolism of [3H]inositol phosphates in AR42J pancreatoma cells: Substance P-induced Ca2+ mobilization in the apparent absence of inositol 1,4,5-trisphosphate 3-kinase activity, J. Biol. Chem. in press.Google Scholar
  18. 18.
    Wilson, D.B., T.E. Bross, S.L. Hofmann, and P.W. Majerus, Hydrolysis of polyphosphoinositides by purified sheep seminal vesicle phospholipase C enzymes, J. Biol. Chem. 259:11718 (1984).PubMedGoogle Scholar
  19. 19.
    Wilson, D.B., T.E. Bross, W.R. Sherman, R.A. Berger, and P.W. Majerus, Inositol cyclic phosphates are produced by cleavage of phosphatidylphosphoinositols (polyphosphoinositides) with purified sheep seminal vesicle phospholipase C enzymes, Proc. Nat. Acad. Sci. USA 82:4013 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    Wilson, D.B., T.M. Connolly, T.E. Bross, P.W. Majerus, W.R. Sherman, A.N. Tyler, L.J. Rubin, and J.E. Brown, Isolation and characterization of the inositol cyclic phosphate products of polyphosphoinositide cleavage by phospholipase C. Physiological effects in permeabilized platelets and Limulus photoreceptor cells, J. Biol. Chem. 260:13496 (1985).PubMedGoogle Scholar
  21. 21.
    Irvine, R.F., A.J. Letcher, D.J. Lander, and M.J. Berridge, Specificity of inositol phosphate-stimulated Ca2+ mobilization from Swiss-mouse 3T3 cells, Biochem. J. 240:301 (1986).PubMedGoogle Scholar
  22. 22.
    Connolly, T.M., D.B. Wilson, T.E. Bross, and P.W. Majerus, Isolation and characterization of the inositol cyclic phosphate products of phosphoinositide cleavage by phospholipase C. Metabolism in cell-free extracts, J. Biol. Chem. 261:122 (1986).PubMedGoogle Scholar
  23. 23.
    Connolly, T.M., V.S. Bansal, T.E. Bross, R.F. Irvine, and P.W. Majerus, The metabolism of tris-and tetraphosphates of inositol by 5-Phosphomonoesterase and 3-kinase enzymes, J. Biol. Chem. 262:2146 (1987).PubMedGoogle Scholar
  24. 24.
    Ishii, H., T.M. Connolly, T.E. Bross, and P.W. Majerus, Inositol cyclic trisphosphate (inositol l:2-cyclic 4,5-trisphosphate) is formed upon thrombin stimulation of human platelets, Proc. Nat. Acad. Sci. USA 83:6397 (1986).PubMedCrossRefGoogle Scholar
  25. 25.
    Tarver, A.P., W.G. King, and S.E. Rittenhouse, Inositol 1,4,5-trisphosphate and inositol 1,2-cyclic 4,5-trisphosphate are minor components of total mass of inositol trisphosphate in thrombin-stimulated platelets, J. Biol. Chem. 262:17268 (1987).PubMedGoogle Scholar
  26. 26.
    Dixon, J.F., and L.E. Hokin, Inositol 1,2-cyclic 4,5-trisphosphate concentration relative to inositol 1,4,5-trisphosphate in pancreatic minilobules on stimulation with carbamylcholine in the absence of lithium. Possible role as a second messenger in long-but not short-term responses, J. Biol. Chem. 262:13892 (1987).PubMedGoogle Scholar
  27. 27.
    Sekar, M.C., J.F. Dixon, and L.E. Hokin, The formation of inositol 1,2-cyclic 4,5-trisphosphate and inositol 1,2-cyclic 4-bisphos-phate on stimulation of mouse pancreatic minilobules with carbamylchol ine, J. Biol. Chem. 262:340 (1987).PubMedGoogle Scholar
  28. 28.
    Dixon, J.F., and L.E. Hokin, Inositol 1,2-cyclic 4,5-trisphosphate is formed in the rat parotid gland on muscarinic stimulation, Biochem. Biophys. Res. Comm. 149:1208 (1987).PubMedCrossRefGoogle Scholar
  29. 29.
    Hughes, A.R., H. Takemura, and J.W. Putney,Jr., Kinetics of inositol 1,4,5-trisphosphate and inositol cyclic 1:2,4,5-trisphosphate metabolism in intact rat parotid acinar cells: Relationship to calcium signalling, J. Biol. Chem. 263:10314 (1988).PubMedGoogle Scholar
  30. 30.
    Aub, D.L., and J.W. Putney, Jr., Metabolism of inositol phosphates in parotid cells: implications for the pathway of the phosphoinositide effect and for the possible messenger role of inositol trisphosphate, Life Sciences 34:1347 (1984).PubMedCrossRefGoogle Scholar
  31. 31.
    Merritt, J.E., and T.J. Rink, Regulation of cytosolic free calcium in fura-2-loaded rat parotid acinar cells, J. Biol. Chem. 262: 17362 (1987).PubMedGoogle Scholar
  32. 32.
    Merritt, J.E., and T.J. Rink, The Effects of substance P and carbachol on inositol tris-and titrakisphosphate formation and cytosolic free calcium in rat parotid acinar cells. A correlation between inositol phosphate levels and calcium entry, J. Biol. Chem. 262:14912 (1987).PubMedGoogle Scholar
  33. 33.
    Aub, D.L., and J.W. Putney, Jr., Mobilization of intracellular calcium by methacholine and inositol 1,4,5-trisphosphate in rat parotid acinar cells, J. Dent. Res. 66:547 (1987).PubMedCrossRefGoogle Scholar
  34. 34.
    Heslop, J.P., R.F. Irvine, A.H. Tashjian, and M.J. Berridge, Inositol tetrakis-and pentakisphosphates in GH4 cells, J. Exp. Biol. 119:395 (1985).PubMedGoogle Scholar
  35. 35.
    Putney, J.W., Jr., A model for receptor-regulated calcium entry, Cell Calcium 7:1 (1986).PubMedCrossRefGoogle Scholar
  36. 36.
    Berridge, M.J., and J.N. Fain, Inhibition of phosphatidyl inositol synthesis and the inactivation of calcium entry after prolonged exposure of the blowfly salivary gland to 5-hydroxytryptamine, Biochem. J. 178:59 (1979).PubMedGoogle Scholar
  37. 37.
    Slack, B.E., J.E. Bell, and D.J. Benos, Inositol 1,4,5-trisphosphate injection mimics fertilization potentials in sea urchin eggs, Am. J. Physiol. 250:C340 (1986).Google Scholar
  38. 38.
    Irvine, R.F., and R.M. Moor, Inositol(1,3,4,5)tetrakisphosphate-induced activation of sea urchin eggs requires the presence of inositol trisphosphate, Biochem. Biophvs. Res. Comm. 146:284 (1987).CrossRefGoogle Scholar
  39. 39.
    Delfert, D.M., S. Hill, H.A. Pershadsingh, and W.R. Sherman, mvo-Inositol 1,4,5-trisphosphate mobilizes Ca2+ from isolated adipocyte endoplasmic reticulum but not from plasma membranes, Biochem. J. 236:37 (1986).PubMedGoogle Scholar
  40. 40.
    Ueda, T., S.H. Church, M.W. Noel, and D.L. Gill, Influence of inositol 1,4,5-trisphosphate and guanine nucleotides on intracellular calcium release within the N1E-115 neuronal cell line, J. Biol. Chem. 261:3184 (1986).PubMedGoogle Scholar
  41. 41.
    Aub, D.L., J.S. McKinney, and J.W. Putney, Jr. Nature of the receptor-regulated calcium pool in the rat parotid gland, J. Physiol. (Lond.) 331:557 (1982).Google Scholar
  42. 42.
    Takemura, H., and J.W. Putney, Jr., Capacitative calcium entry in parotid acinar cells, Nature, submitted.Google Scholar
  43. 43.
    Grynkiewicz, G., M. Poenie, and R.Y. Tsien, A new generation of Ca2+ indicators with indicators with greatly improved fluorescence properties, J. Biol. Chem. 260:3440 (1986).Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • James W. PutneyJr.
    • 1
  • Arlene R. Hughes
    • 1
  • Debra A. Horstman
    • 1
  • Haruo Takemura
    • 1
  1. 1.Calcium Regulation Section, Laboratory of Cellular and Molecular PharmacologyNational Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUSA

Personalised recommendations