Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Back in the water: the return of the inositol phosphates

Nature Reviews Molecular Cell Biology volume 2, pages 327–338 (2001)Cite this article

Key Points

  • There has been great progress recently in our knowledge of potential functions for inositol phosphates (other than inositol-1,4,5-trisphosphate Ins(1,4,5)P3), as well as in our understanding of the enzymes that metabolize them, although we still remain uncertain about many of the details of the metabolic pathways.

  • Inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) has several functions in animal cells, where it is synthesized from Ins(1,4,5)P3 by a family of 3-kinases that have evolved quite recently in animals.

  • Inositol-3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4) functions as a negative regulator of chloride efflux in epithelial cells. Although the molecular details are not all clear, the implications for cystic fibrosis have a possible clinical relevance.

  • Inositol-1,4,5,6-tetrakisphosphate (Ins(1,4,5,6)P4) might also have a physiological role, indicated by its unusual metabolism, but we do not yet know what that role is.

  • Inositol-1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) is a metabolic 'hub' in inositol phosphates, but has no clearly defined function other than its suggested role as a modulator of haemoglobin in erythrocytes of a few animal species, a role that might be more complex than has previously been suspected.

  • Inositol hexakisphosphate (InsP6) has been suggested to fulfill many functions, and recently there have been several new possibilities proposed. These include K+ channel regulation in plant guard cells, controlling messenger RNA transport from the nucleus, regulating DNA repair and a role in endocytosis (possibly involving an InsP6-regulated protein kinase).

  • InsP7 and InsP8 are the newest members of the physiological inositol phosphate repertoire, which might function as drivers of membrane–protein interactions by acting as a localized energy source.

Abstract

Following the discovery of inositol-1,4,5-trisphosphate as a second messenger, many other inositol phosphates were discovered in quick succession, with some understanding of their synthesis pathways and a few guesses at their possible functions. But then it all seemed to go comparatively quiet, with an explosion of interest in the inositol lipids. Now the water-soluble phase is once again becoming a focus of interest. Old and new data point to a new vista of inositol phosphates, with functions in many diverse aspects of cell biology, such as ion-channel physiology, membrane dynamics and nuclear signalling.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathways of metabolism of inositol phosphates.
Figure 2: Consequences of inositol-1,3,4,5-tetrakisphosphate generation.

References

  1. Posternak, S. Sur la synthése de l'ether hexaphosphorique de l'inosite avec le principe phospho-organique de réserve des plantes vertes. Compt. Rend. Acad. Sci. 169, 138–140 (1919).

    CAS  Google Scholar 

  2. Streb, H., Irvine, R. F., Berridge, M. J. & Schulz, I. Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306, 67–69 ( 1983).

    Article  CAS  PubMed  Google Scholar 

  3. Irvine, R. F., Letcher, A. J., Lander, D. J. & Downes, C. P. Inositol trisphosphates in carbachol-stimulated rat parotid glands. Biochem. J. 223, 237–243 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Batty, I. R., Nahorski, S. R. & Irvine, R. F. Rapid formation of inositol 1,3,4,5-tetrakisphosphate following muscarinic receptor stimulation of rat cortical slices. Biochem. J. 232, 211–215 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Heslop, J. P., Irvine, R. F., Tashjian, A. H., Jr & Berridge, M. J. Inositol tetrakis- and pentakisphosphates in GH4 cells. J. Exp. Biol. 119, 395– 401 (1985).

    CAS  PubMed  Google Scholar 

  6. Shears, S. B. Metabolism of the inositol phosphates produced upon receptor activation. Biochem. J. 260, 313–324 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Whitman, M., Downes, C. P., Keeler, M., Keller, T. & Cantley, L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332, 644–646 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  8. Traynor-Kaplan, A. E., Harris, A. L., Thompson, B. L., Taylor, P. & Sklar, L. A. An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature 334, 353–356 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Hermosura, M. C. et al. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature 408, 735–740 (2000). The demonstration that the ability of Ins(1,3,4,5)P 4 to protect Ins(1,4,5)P 3 against hydrolysis might have an important physiological role.

    Article  CAS  PubMed  Google Scholar 

  10. Connolly, T. M., Bansal, V. S., Bross, T. E., Irvine, R. F. & Majerus, P. W. The metabolism of tris- and tetraphosphates of inositol by 5-phosphomonoesterase and 3-kinase enzymes. J. Biol. Chem. 262, 2146–2149 ( 1987).

    CAS  PubMed  Google Scholar 

  11. Irvine, R. Inositol phosphates: Does IP4 run a protection racket? Curr Biol 11, R172–R175 ( 2001).

    Article  CAS  PubMed  Google Scholar 

  12. Luckhoff, A. & Clapham, D. E. Inositol 1,3,4,5-tetrakisphosphate activates an endothelial Ca2+-permeable channel. Nature 355, 356–358 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  13. Tsubokawa, H., Oguro, K., Robinson, H. P. C., Masuzawa, T. & Kawai, N. Intracellular inositol 1,3,4,5-tetrakisphosphate enhances the calcium current in hippocampal CA1 neurones of the gerbil after ischaemia. J. Physiol. 497, 67– 78 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Szinyei, C., Behnisch, T., Reiser, G. & Reymann, K. G. Inositol 1,3,4,5-tetrakisphosphate enhances long-term potentiation by regulating Ca2+ entry in rat hippocampus. J. Physiol. (Lond.) 516, 855–868 (1999).

    Article  CAS  Google Scholar 

  15. Jun, K. et al. Enhanced hippocampal CA1 LTP but normal spatial learning in inositol 1,4,5-trisphosphate 3-kinase(A)-deficient mice. Learn. Mem. 5, 317–330 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Fujii, S., Matsumoto, M., Igarashi, K., Kato, H. & Mikoshiba, K. Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors . Learn. Mem. 7, 312–320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bird, G. S. & Putney, J. W., Jr Effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-activated Ca2+ signaling in mouse lacrimal acinar cells. J. Biol. Chem. 271, 6766–6770 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  18. Gawler, D. J., Potter, B. V. L. & Nahorski, S. R. Inositol 1,3,4,5-tetrakisphosphate-induced release of intracellular Ca2+ in SH-SY5Y neuroblastoma cells. Biochem J 272, 519–524 ( 1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Smith, P. M., Harmer, A. R., Letcher, A. J. & Irvine, R. F. The effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-induced Ca2+ mobilisation in freshly isolated and cultured mouse lacrimal acinar cells. Biochem. J. 347, 77– 82 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Morris, A. P., Gallacher, D. V., Irvine, R. F. & Petersen, O. H. Synergism of inositol trisphosphate and tetrakisphosphate in activating Ca2+-dependent K+ channels. Nature 330, 653–655 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Bird, G. S. et al. Activation of Ca2+ entry into acinar cells by a non-phosphorylatable inositol trisphosphate. Nature 352, 162–165 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Loomis-Husselbee, J. W., Cullen, P. J., Dreikausen, U. E., Irvine, R. F. & Dawson, A. P. Synergistic effects of inositol 1,3,4,5-tetrakisphosphate on inositol 2,4,5-triphosphate-stimulated Ca2+ release do not involve direct interaction of inositol 1,3,4,5-tetrakisphosphate with inositol triphosphate-binding sites. Biochem. J. 314, 811–816 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Loomis-Husselbee, J. W. et al. Modulation of Ins(2,4,5)P3-stimulated Ca2+ mobilization by Ins(1,3,4,5)P4: enhancement by activated G-proteins, and evidence for the involvement of a GAP1 protein, a putative Ins(1,3,4,5)P4 receptor. Biochem. J. 331 , 947–952 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cullen, P. J. et al. Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family. Nature 376, 527–530 (1995).The cloning of a putative (and still promising) receptor for Ins(1,3,4,5)P 4.

    Article  CAS  PubMed  Google Scholar 

  25. Lockyer, P. J. et al. Identification of the ras GTPase-activating protein GAP1m as a phosphatidylinositol-3,4,5-trisphosphate-binding protein in vivo. Curr. Biol. 9, 265– 268 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Cozier, G. E. et al. GAP1IP4BP contains a novel group I pleckstrin homology domain that directs constituitive plasma membrane association. J. Biol. Chem. 275, 28261–28268 (2000).

    CAS  PubMed  Google Scholar 

  27. Kachintorn, U., Vajanaphanich, M., Barrett, K. E. & Traynor Kaplan, A. E. Elevation of inositol tetrakisphosphate parallels inhibition of Ca2+-dependent Cl− secretion in T84 cells. Am. J. Physiol. 264, C671–C676 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Vajanaphanich, M. et al. Long-term uncoupling of chloride secretion from intracellular calcium levels by Ins(3,4,5,6)P4 . Nature 371, 711–714 (1994). The definitive demonstration that Ins(3,4,5,6)P 4 is likely to participate in the physiological regulation of chloride efflux.

    Article  CAS  PubMed  Google Scholar 

  29. Ho, M. W. Y., Carew, M. A., Yang, X. & Shears, S. B. in Biology of Phosphoinositides (ed. Cockcoft, S.) 298–319 (Oxford Univ. Press, Oxford, 2000).

    Google Scholar 

  30. Xie, W. et al. Inositol 3,4,5,6-tetrakisphosphate inhibits the calmodulin-dependent protein kinase II-activated chloride conductance in T84 colonic epithelial cells. J. Biol. Chem. 271, 14092– 14097 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Ismailov, I. I. et al. A biologic function for an 'orphan' messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels. Proc. Natl Acad. Sci. USA 93, 10505–10509 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ho, M. W. Y., Kaetzel, M. A., Armstrong, D. L. & Shears, S. B. Regulation of a human chloride channel: a paradigm for intergrating input from calcium, CaMKII and Ins(3,4,5,6)P4 . J. Biol. Chem. (in the press).

  33. Xie, W. et al. Regulation of Ca2+-dependent Cl− conductance in a human colonic epithelial cell line (T84): cross-talk between Ins(3,4,5,6)P4 and protein phosphatases. J. Physiol. (Lond.) 510, 661–673 ( 1998).

    Article  CAS  Google Scholar 

  34. Yang, X. et al. Inositol 1,3,4-trisphosphate acts in vivo as a specific regulator of cellular signaling by inositol 3,4,5,6-tetrakisphosphate. J. Biol. Chem. 274, 18973–18980 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Oliver, K. G., Putney, J. W., Jr Obie, J. F. & Shears, S. B. The interconversion of inositol 1,3,4,5,6-pentakisphosphate and inositol tetrakisphosphates in AR4-2J cells. J. Biol. Chem. 267, 21528 –21534 (1992).

    CAS  PubMed  Google Scholar 

  36. Mattingly, R. R., Stephens, L. R., Irvine, R. F. & Garrison, J. C. Effects of transformation with the v-src oncogene on inositol phosphate metabolism in rat-1 fibroblasts. d-myo-inositol 1,4,5,6-tetrakisphosphate is increased in v-src transformed rat-1 fibroblasts and can be synthesized from d-myo-inositol 1,3,4-trisphosphate in cytosolic extracts. J. Biol. Chem. 266, 15144–15153 (1991).

    CAS  PubMed  Google Scholar 

  37. Eckmann, L. et al. d-myo-Inositol 1,4,5,6-tetrakisphosphate produced in human intestinal epithelial cells in response to Salmonella invasion inhibits phosphoinositide 3-kinase signaling pathways. Proc. Natl Acad. Sci. USA 94, 14456–14460 (1997).The suggestion that Ins(1,4,5,6)P 4 might have physiological significance, as mediating some of the effects of Salmonella infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Majerus, P. W., Kisseleva, M. V. & Norris, F. A. The role of phosphatases in inositol signaling reactions . J. Biol. Chem. 274, 10669– 10672 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Norris, F. A., Wilson, M. P., Wallis, T. S., Galyov, E. E. & Majerus, P. W. SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase . Proc. Natl Acad. Sci. USA 95, 14057– 14059 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Feng, Y., Wente, S. R. & Majerus, P. W. Overexpression of the inositol phosphatse SopB in human 293 cells stimulates cellular chloride influx and inhibits nuclear mRNA transport. Proc. Natl Acad. Sci. USA 98, 875–879 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou, D., Chen, L. M., Hernandez, L., Shears, S. B. & Galan, J. E. A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. Mol. Microbiol. 39, 248–260 ( 2001).

    Article  CAS  PubMed  Google Scholar 

  42. Johnson, L. F. & Tate, M. E. The structure of 'phytic acids'. Can. J. Chem. 47, 63– 73 (1969).

    Article  CAS  Google Scholar 

  43. Stephens, L. R. et al. Myo-inositol pentakisphosphates. Structure, biological occurrence and phosphorylation to myo-inositol hexakisphosphate. Biochem. J. 275, 485–499 ( 1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guse, A. H. & Emmrich, F. T-cell receptor-mediated metabolism of inositol polyphosphates in Jurkat T-lymphocytes. Identification of a d-myo-inositol 1,2,3,4,6-pentakisphosphate-2-phosphomonoesterase activity, a d-myo-inositol 1,3,4,5,6-pentakisphosphate-1/3-phosphatase activity and a d/l-myo-inositol 1,2,4,5,6-pentakisphosphate-1/3-kinase activity. J. Biol. Chem. 266, 24498– 24502 (1991).

    CAS  PubMed  Google Scholar 

  45. McConnell, F. M., Stephens, L. R. & Shears, S. B. Multiple isomers of inositol pentakisphosphate in Epstein-Barr-virus-transformed (T5-1) B-lymphocytes. Identification of inositol 1,3,4,5,6-pentakisphosphate, d-inositol 1,2,4,5,6-pentakisphosphate and l-inositol 1,2,4,5,6-pentakisphosphate. Biochem. J. 280, 323–329 ( 1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Coates, M. L. Hemoglobin function in the vertebrates: an evolutionary model. J. Mol. Evol. 6, 285–307 (1975).

    Article  CAS  PubMed  Google Scholar 

  47. Bartlett, G. R. Phosphate compounds in reptilian and avian red blood cells; developmental changes. Comp. Biochem Physiol. A 61, 191 –202 (1978).

    Article  Google Scholar 

  48. Isaacks, R. E., Harkness, D. R. & Witham, P. R. Relationship between the major phosphorylated metabolic intermediates and oxygen affinity of whole blood in the loggerhead (Caretta caretta) and the green sea turtle (Chelonia mydas) during development . Dev. Biol. 62, 344–353 (1978).

    Article  CAS  PubMed  Google Scholar 

  49. Isaacks, R. E., Lai, L. L., Goldman, P. H. & Kim, C. Y. Studies on avian erythrocyte metabolism. XVI. Accumulation of 2,3-bisphosphoglycerate with shifts in oxygen affinity of chicken erythrocytes. Arch. Biochem. Biophys. 257, 177–185 ( 1987).

    Article  CAS  PubMed  Google Scholar 

  50. Val, A. L., Affonso, E. G., Souza, R. H. D., Dealmeidaval, V. M. F. & Demoura, M. A. F. Inositol pentaphosphate in the erythrocytes of an Amazonian fish, the Pirarucu ( Arapaima gigas). Can. J. Zool. 70, 852 –855 (1992).

    Article  CAS  Google Scholar 

  51. Lemtiri-Chlieh, F., MacRobbie, E. A. & Brearley, C. A. Inositol hexakisphosphate is a physiological signal regulating the K+-inward rectifying conductance in guard cells . Proc. Natl Acad. Sci. USA 97, 8687– 8692 (2000).A new function for InsP 6 in plants.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pittet, D., Schlegel, W., Lew, D. P., Monod, A. & Mayr, G. W. Mass changes in inositol tetrakis- and pentakisphosphate isomers induced by chemotactic peptide stimulation in HL-60 cells. J. Biol. Chem. 264, 18489–18493 (1989).

    CAS  PubMed  Google Scholar 

  53. Szwergold, B. S., Graham, R. A. & Brown, T. R. Observation of inositol pentakis- and hexakis-phosphates in mammalian tissues by 31P NMR. Biochem. Biophys. Res. Commun. 149, 874–881 (1987).

    Article  CAS  PubMed  Google Scholar 

  54. Martin, J. B., Foray, M. F., Klein, G. & Satre, M. Identification of inositol hexaphosphate in 31P-NMR spectra of Dictyostelium discoideum amoebae. Relevance to intracellular pH determination. Biochim. Biophys. Acta 931, 16–25 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Stuart, J. A., Anderson, K. L., French, P. J., Kirk, C. J. & Michell, R. H. The intracellular distribution of inositol polyphosphates in HL60 promyeloid cells. Biochem. J. 303, 517–525 ( 1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Larsson, O. et al. Inhibition of phosphatases and increased Ca2+ channel activity by inositol hexakisphosphate. Science 278, 471–474 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Efanov, A. M., Zaitsev, S. V. & Berggren, P. O. Inositol hexakisphosphate stimulates non-Ca2+-mediated and primes Ca2+-mediated exocytosis of insulin by activation of protein kinase C. Proc. Natl Acad. Sci. USA 94, 4435–4439 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fukuda, M., Kojima, T., Aruga, J., Niinobe, M. & Mikoshiba, K. Functional diversity of C2 domains of synaptotagmin family. Mutational analysis of inositol high polyphosphate binding domain . J. Biol. Chem. 270, 26523– 26527 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Mehrotra, B., Myszka, D. G. & Prestwich, G. D. Binding kinetics and ligand specificity for the interactions of the C2B domain of synaptogmin II with inositol polyphosphates and phosphoinositides . Biochemistry 39, 9679– 9686 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Voglmaier, S. M. et al. Inositol hexakisphosphate receptor identified as the clathrin assembly protein AP-2. Biochem. Biophys. Res. Commun. 187, 158–163 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Ye, W., Ali, N., Bembenek, M. E., Shears, S. B. & Lafer, E. M. Inhibition of clathrin assembly by high affinity binding of specific inositol polyphosphates to the synapse-specific clathrin assembly protein AP-3. J. Biol. Chem. 270, 1564–1568 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Norris, F. A., Ungewickell, E. & Majerus, P. W. Inositol hexakisphosphate binds to clathrin assembly protein 3 (AP-3/AP180) and inhibits clathrin cage assembly in vitro. J. Biol. Chem. 270, 214–217 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Gaidarov, I., Krupnick, J. G., Falck, J. R., Benovic, J. L. & Keen, J. H. Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO J. 18, 871–881 ( 1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shears, S. B. Assessing the functional omnipotence of inositol hexakisphophosphate. Cell Signalling 13, 151–158 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Graf, E., Empson, K. L. & Eaton, J. W. Phytic acid. A natural antioxidant. J. Biol. Chem. 262, 1164–1150 (1987).

    Google Scholar 

  66. Hawkins, P. T. et al. Inhibition of iron-catalysed hydroxyl radical formation by inositol polyphosphates: a possible physiological function for myo-inositol hexakisphosphate. Biochem. J. 294, 929– 934 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Spiers, I. D. et al. Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/−)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates. Carbohydr. Res. 282, 81–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Hilton, J. M. et al. Phosphorylation of a synaptic vesicle associated protein by an inositol hexakisphosphate-regulated protein kinase. J. Biol. Chem. (in the press).One of the 'new wave' papers of InsP 6 actions — a convincing demonstration that it might act through a protein kinase.

  69. Stephens, L. R. & Irvine, R. F. Stepwise phosphorylation of myo-inositol leading to myo-inositol hexakisphosphate in Dictyostelium . Nature 346, 580–583 (1990).

    Article  CAS  PubMed  Google Scholar 

  70. Van der Kaay, J., Wesseling, J. & Van Haastert, P. J. Nucleus-associated phosphorylation of Ins(1,4,5)P 3 to InsP6 in Dictyostelium. Biochem. J. 312, 911–917 ( 1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. York, J. D., Odom, A. R., Murphy, R., Ives, E. B. & Wente, S. R. A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285, 96–100 ( 1999).InsP 6 is suggested to be involved in mRNA export from the nucleus.

    Article  CAS  PubMed  Google Scholar 

  72. Odom, A. R., Stahlberg, A., Wente, S. R. & York, J. D. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287, 2026– 2029 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Ongusaha, P. P., Hughes, P. J., Davey, J. & Michell, R. H. Inositol hexakisphosphate in Schizosaccharomyces pombe: synthesis from Ins(1,4,5)P3 and osmotic regulation. Biochem. J. 335, 671–679 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Saiardi, A., Erdjument-Bromage, H., Snowman, A. M., Tempst, P. & Snyder, S. H. Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases. Curr. Biol. 9, 1323– 1326 (1999).The definition of a new family of inositol phosphate kinases that includes 'InsP multikinase', InsP 6 kinase and Ins(1,4,5)P 3 3-kinase.

    Article  CAS  PubMed  Google Scholar 

  75. Saiardi, A., Caffrey, J. J., Snyder, S. H. & Shears, S. B. Inositol polyphosphate multikinase (ArgRIII) determines nuclear mRNA export in Saccharomyces cerevisiae. FEBS Lett. 468, 28–32 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Saiardi, A., Caffrey, J. J., Snyder, S. H. & Shears, S. B. The inositol hexakisphosphate kinase family. Catalytic flexibility and function in yeast vacuole biogenesis. J. Biol. Chem. 275, 24686–24692 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Ives, E. B., Nichols, J., Wente, S. R. & York, J. D. Biochemical and functional characterization of inositol 1,3,4,5,6- pentakisphosphate 2-kinases. J. Biol. Chem. 275, 36575– 36583 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Hanakahi, L. A., Bartlet-Jones, M., Chappell, C., Pappin, D. & West, S. C. Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell 102, 721–729 (2000). InsP 6 is shown to be a possible regulator of DNA repair.

    Article  CAS  PubMed  Google Scholar 

  79. Stephens, L. et al. The detection, purification, structural characterization, and metabolism of diphosphoinositol pentakisphosphate(s) and bisdiphosphoinositol tetrakisphosphate(s). J. Biol. Chem. 268, 4009–4015 (1993).

    CAS  PubMed  Google Scholar 

  80. Menniti, F. S., Miller, R. N., Putney, J. W., Jr & Shears, S. B. Turnover of inositol polyphosphate pyrophosphates in pancreatoma cells. J. Biol. Chem. 268, 3850 –3856 (1993).References 79 and 80 describe the discovery of InsP 7 and InsP 8.

    CAS  PubMed  Google Scholar 

  81. Albert, C. et al. Biological variability in the structures of diphosphoinositol polyphosphates in Dictyostelium discoideum and mammalian cells. Biochem. J. 327, 553–560 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Laussmann, T., Reddy, K. M., Reddy, K. K., Falck, J. R. & Vogel, G. Diphospho-myo-inositol phosphates from Dictyostelium identified as d-6-diphospho-myo-inositol pentakisphosphate and d-5,6-bisdiphospho-myo-inositol tetrakisphosphate . Biochem. J. 322, 31–33 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Voglmaier, S. M. et al. Purified inositol hexakisphosphate kinase is an ATP synthase: diphosphoinositol pentakisphosphate as a high-energy phosphate donor. Proc. Natl Acad. Sci. USA 93, 4305– 4310 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Glennon, M. C. & Shears, S. B. Turnover of inositol pentakisphosphates, inositol hexakisphosphate and diphosphoinositol polyphosphates in primary cultured hepatocytes. Biochem. J. 293, 583–590 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Safrany, S. T. & Shears, S. B. Turnover of bis-diphosphoinositol tetrakisphosphate in a smooth muscle cell line is regulated by β2-adrenergic receptors through a cAMP-mediated, A-kinase-independent mechanism. EMBO J. 17, 1710– 1716 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schell, M. J. et al. PiUS (Pi uptake stimulator) is an inositol hexakisphosphate kinase. FEBS Lett. 461, 169– 172 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Huang, C. F., Voglmaier, S. M., Bembenek, M. E., Saiardi, A. & Snyder, S. H. Identification and purification of diphosphoinositol pentakisphosphate kinase, which synthesizes the inositol pyrophosphate bis(diphospho)inositol tetrakisphosphate. Biochemistry 37, 14998–15004 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  88. El Bakkoury, M., Dubois, E. & Messenguy, F. Recruitment of the yeast MADS-box proteins, ArgRI and Mcm1 by the pleiotropic factor ArgRIII is required for their stability. Mol. Microbiol. 35, 15–31 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Dubois, E., Dewaste, V., Erneux, C. & Messenguy, F. Inositol polyphosphate kinase activity of Arg82/ArgRIII is not required for the regulation of the arginine metabolism in yeast. FEBS Lett. 486, 300–304 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Saiardi, A. et al. Mammalian inositol polyphosphate multikinase synthesises inositol (1,4,5)–trisphosphate and an inositol pyrophosphate. Proc. Natl Acad. Sci. USA 98, 2306–2311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kuo, M. H., Nadeau, E. T. & Grayhack, E. J. Multiple phosphorylated forms of the Saccharomyces cerevisiae Mcm1 protein include an isoform induced in response to high salt concentrations. Mol. Cell. Biol. 17, 819–832 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Agranoff, B. W. Cyclitol confusion. Trends Biochem. Sci. 3, N283–N285 (1978).

    Article  CAS  Google Scholar 

  93. Stephens, L. et al. l-myo-inositol 1,4,5,6-tetrakisphosphate is present in both mammalian and avian cells. Biochem. J. 249, 271–282 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Carew, M. A., Yang, X., Schultz, C. & Shears, S. B. myo-inositol 3,4,5,6-tetrakisphosphate inhibits an apical calcium-activated chloride conductance in polarized monolayers of a cystic fibrosis cell line. J. Biol. Chem. 275, 26906–26913 ( 2000).

    CAS  PubMed  Google Scholar 

  95. Eisenberg, F. J. d-myoinositol 1-phosphate as the product of cyclization of glucose 6-phosphate and substrate for a specific phosphatase in rat testis. J. Biol. Chem. 242, 1375–1382 ( 1967).

    CAS  PubMed  Google Scholar 

  96. Bertsch, U. et al. The second messenger binding site of inositol 1,4,5-trisphosphate 3-kinase is centered in the catalytic domain and related to the inositol trisphosphate receptor site. J. Biol. Chem. 275, 1557– 1564 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Communi, D., Vanweyenberg, V. & Erneux, C. d-myo-inositol 1,4,5-trisphosphate 3-kinase A is activated by receptor activation through a calcium:calmodulin-dependent protein kinase II phosphorylation mechanism. EMBO J. 16, 1943–1952 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Communi, D., Dewaste, V. & Erneux, C. Calcium-calmodulin-dependent protein kinase II and protein kinase C-mediated phosphorylation and activation of d-myo-inositol 1,4, 5-trisphosphate 3-kinase B in astrocytes. J. Biol. Chem. 274, 14734–14742 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Dewaste, V. et al. Cloning and expression of a cDNA encoding human inositol 1,4,5-trisphosphate 3-kinase C. Biochem. J. 352, 343– 351 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Soriano, S. et al. Membrane association, localization and topology of rat inositol 1,4,5-trisphosphate 3-kinase B: implications for membrane traffic and Ca2+ homoeostasis. Biochem. J. 324, 579–589 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wilson, M. P. & Majerus, P. W. Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression of the recombinant enzyme. J. Biol. Chem. 271, 11904–11910 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Yang, X. & Shears, S. B. Multitasking in signal transduction by a promiscuous human Ins(3,4,5, 6)P4 1-kinase/Ins(1,3,4)P 3 5/6-kinase. Biochem. J. 351, 551 –555 (2000).The demonstration that Ins(1,3,4)P 3 6/5-kinase and Ins(3,4,5,6)P 4 1-kinase are the same enzyme, thus clarifying how increases in Ins(1,3,4)P 3 lead to increases in Ins(3,4,5,6)P 4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Stephens, L. R. & Downes, C. P. Product–precursor relationships amongst inositol polyphosphates. Incorporation of [32P]Pi into myo-inositol 1,3,4,6-tetrakisphosphate, myo-inositol 1,3,4,5-tetrakisphosphate, myo-inositol 3,4,5,6- tetrakisphosphate and myo-inositol 1,3,4,5,6-pentakisphosphate in intact avian erythrocytes. Biochem. J. 265, 435–452 ( 1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Stephens, L. R., Hughes, K. T. & Irvine, R. F. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 351, 33–39 (1991).

    Article  CAS  PubMed  Google Scholar 

  105. Brearley, C. A. & Hanke, D. E. Pathway of synthesis of 3,4- and 4,5-phosphorylated phosphatidylinositols in the duckweed Spirodela polyrhiza L. Biochem. J. 290, 145– 150 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Whiteford, C. C., Brearley, C. A. & Ulug, E. T. Phosphatidylinositol 3,5-bisphosphate defines a novel PI 3-kinase pathway in resting mouse fibroblasts. Biochem. J. 323, 597–601 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Brearley, C. A. & Hanke, D. E. Metabolic evidence for the order of addition of individual phosphate esters in the myo-inositol moiety of inositol hexakisphosphate in the duckweed Spirodela polyrhiza L. Biochem. J. 314, 227– 233 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Irvine, R. F., Letcher, A. J., Heslop, J. P. & Berridge, M. J. The inositol tris/tetrakisphosphate pathway — demonstration of Ins(1,4,5)P3 3-kinase activity in animal tissues. Nature 320, 631–634 (1986).

    Article  CAS  PubMed  Google Scholar 

  109. Balla, T., Sim, S. S., Baukal, A. J., Rhee, S. G. & Catt, K. J. Inositol polyphosphates are not increased by overexpression of Ins(1,4,5)P3 3-kinase but show cell-cycle dependent changes in growth factor-stimulated fibroblasts. Mol. Biol. Cell 5, 17–27 ( 1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nogimori, K., Menniti, F. S. & Putney, J. W., Jr Identification in extracts from AR4-2J cells of inositol 1,4,5-trisphosphate by its susceptibility to inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase. Biochem. J. 269, 195–200 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bird, G. J., Oliver, K. G., Horstman, D. A., Obie, J. & Putney, J. W., Jr Relationship between the calcium-mobilizing action of inositol 1,4,5-trisphosphate in permeable AR4-2J cells and the estimated levels of inositol 1,4,5-trisphosphate in intact AR4-2J cells. Biochem. J. 273, 541– 546 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Stephens, L. R., Kay, R. R. & Irvine, R. F. A myo-inositol d-3 hydroxykinase activity in Dictyostelium. Biochem. J. 272, 201–210 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Loewus, M. W. et al. Enanantiomeric form of myo-inositol 1-phosphate produced by myo-inositol 1-phosphate synthetase and myo-inositol kinase in higher plants . Plant Physiol. 70, 1661– 1663 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Verjans, B. et al. Cloning and expression in Escherichia coli of a dog thyroid cDNA encoding a novel inositol 1,4,5-trisphosphate 5-phosphatase. Biochem. J. 300, 85–90 ( 1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Erneux, C., Govaerts, C., Communi, D. & Pesesse, X. The diversity and possible functions of the inositol polyphosphate 5-phosphatases . Biochim. Biophys. Acta 1436, 185– 199 (1998).

    Article  CAS  PubMed  Google Scholar 

  116. Craxton, A., Caffrey, J. J., Burkhart, W., Safrany, S. T. & Shears, S. B. Molecular cloning and expression of a rat hepatic multiple inositol polyphosphate phosphatase. Biochem. J. 328, 75–81 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ali, N., Craxton, A. & Shears, S. B. Hepatic Ins(1,3,4,5)P4 3-phosphatase is compartmentalized inside endoplasmic reticulum. J. Biol. Chem. 268, 6161–6167 ( 1993).

    CAS  PubMed  Google Scholar 

  118. Chi, H. et al. Targeted deletion of Minpp1 provides new insight into the activity of multiple inositol polyphosphate phosphatase in vivo. Mol. Cell. Biol. 20, 6496–6507 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Safrany, S. T. et al. A novel context for the 'MutT' module, a guardian of cell integrity, in a diphosphoinositol polyphosphate phosphohydrolase. EMBO J. 17, 6599–6607 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Caffrey, J. J., Safrany, S. T., Yang, X. & Shears, S. B. Discovery of molecular and catalytic diversity among human diphosphoinositol-polyphosphate phosphohydrolases. An expanding Nudt family. J. Biol. Chem. 275, 12730–12736 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Caffrey, J. J. & Shears, S. B. Genetic rationale for microheterogeneity of human diphosphoinositol polyphosphate phosphohydrolase Type 2. Genetics (in the press).

Download references

Acknowledgements

We are grateful to our many colleagues for helpful discussions and supply of pre-prints, but in particular we would like to thank S. Shears, A. Saiardi, B. Michell, P. Hawkins and G. Ihrke. R.F.I. is supported by the Royal Society and M.J.S. by the Wellcome Trust. The poem by O. Nash is reproduced with the kind permission of L. Nash Smith and I. Nash Eberstadt.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1QJ, UK

    Robin F. Irvine & Michael J. Schell

Authors
  1. Robin F. Irvine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J. Schell
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

The turtle lives 'twixt plated decks Which practically conceal its sex. I think it clever of the turtle In such a fix to be so fertile. Ogden Nash (1902–1971)

Related links

Related links

DATABASE LINKS

Src

Ins (1,4,5)P3 3-kinase

CaM

CaMKII

phospholipase C

Ins(1,4,5)P3 receptors

GAP1m

CLCA1

Ins(3,4,5,6)P4 1-kinase

SopB

protein kinase C

synaptotagmins

pacsin

phosphoinositide-specific phospholipase C

DNA-dependent protein kinase

AP-180

AP-2

Arg82

Arg80

Mcm1

Arg81

MIPP

GAP1IP4BP

FURTHER INFORMATION

Shears' lab

Pirarucu

Another view of inositol phosphate metabolism

Sources of inositol phosphates

IUBMB nomenclature of inositides

LINKS

Sources of inositol phosphates

Glossary

VMAX (Vmax).

The maximum velocity (that is, the rate) at which an enzyme can catalyse a reaction. This occurs when the substrate is at a concentration that saturates the enzyme, and the concentration of the enzymatic product is low.

COINCIDENCE DETECTION

The process whereby a cell responds differently to a signal if another signal is received simultaneously (or just before). This is particularly important in the brain, where different spatial, temporal and chemical inputs to a neuron can alter the neuron's output.

LTP

Long-term potentiation is a specific example of coincidence detection, whereby the high frequency stimulation of a neuron increases the magnitude of subsequent responses, an effect that can last for days. LTP is believed to underlie some kinds of learning and memory.

INS(1,4,5)P3 RECEPTORS

Ca2+ channels located on the endoplasmic reticulum which, when Ins(1,4,5)P3 binds to them, open to release stored Ca2+. There are three subtypes (I, II and III); all have similar structures and functions.

STORE-OPERATED CA2+ ENTRY

The activation of a Ca2+ channel in the plasma membrane in response to the depletion of Ca2+ levels in the endoplasmic reticulum (ER). Decreases in the levels of stored Ca2+ inside the ER somehow signal to the plasma membrane channels (store-operated calcium channels, or SOCs).

L-1210 CELLS

A mouse lymphoma cell line that grows readily in suspension, a property useful for studying Ca2+ homeostasis in permeabilized cells.

T-84 CELLS

A colonic epithelial cell line.

PATCH-CLAMP

The technique of attaching a pipette to the outside of a cell, and either pulling the small piece of membrane captured within it off the cell ('excised patch') or rupturing this piece, thus making the interior of the cell continuous with the inside of the pipette ('whole cell patch').

PI3K AND PTDINS(3,4,5)P3

The phosphatidylinositol 3-kinases are a family of enzymes that phosphorylate the 3-position on inositol lipids. The type I varieties are the most relevant for signal transduction because they are receptor-regulated; they prefer phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) as a substrate and thus make the second messenger PtdIns(3,4,5)P3.

GUARD CELLS

The cells found on the underside of plant leaves, which pair up to form stomata, or leaf pores. Guard cells control the size of the stomata, and thus in turn regulate gas exchange in the leaf.

ABSCISIC ACID

A plant hormone originally discovered (and named) for its ability to regulate leaf detachment; also a key regulator of guard cell shape (and thus gas exchange) in the leaf.

SYNAPTOTAGMINS

A group of Ca2+-binding proteins that are generally understood to be involved with the secretion of granules and vesicles, especially in the nervous system.

AP-2 AND AP-180

Two members of a family of so-called 'clathrin adaptor proteins', which facilitate the early stages of endocytic vesicle formation through their ability to bind clathrin coats.

ARRESTIN

Protein that, when phosphorylated, associates with G-protein-coupled receptors, thereby inhibiting the receptors' actions.

MADS BOX

A superfamily of transcription factors (including Mcm1, agamous, deficiens and serum response factor), which bind DNA and control a plethora of cellular functions.

NUDT DOMAIN

Nudix-type domain, previously known as a MutT domain. Discovered in a group of enzymes that protect cells from threats such as oxygen radicals.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Irvine, R., Schell, M. Back in the water: the return of the inositol phosphates. Nat Rev Mol Cell Biol 2, 327–338 (2001). https://doi.org/10.1038/35073015

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35073015

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing