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.

  • Letter
  • Published:

InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase

Nature volume 408, pages 735–740 (2000)Cite this article

Abstract

Receptor-mediated generation of inositol 1,4,5-trisphosphate (InsP3) initiates Ca2+ release from intracellular stores and the subsequent activation of store-operated calcium influx1. InsP3 is metabolized within seconds by 5-phosphatase and 3-kinase2, yielding Ins(1,4)P2 and inositol 1,3,4,5-tetrakisphosphate (InsP4), respectively. Some studies have suggested that InsP4 controls Ca2+ influx in combination with InsP3 (refs 3 and 4), but another study did not find the same result5. Some of the apparent conflicts between these previous studies have been resolved6; however, the physiological function of InsP4 remains elusive7,8. Here we have investigated the function of InsP4 in Ca2+ influx in the mast cell line RBL-2H3, and we show that InsP4 inhibits InsP3 metabolism through InsP3 5-phosphatase, thereby facilitating the activation of the store-operated Ca2+ current ICRAC (ref. 9). Physiologically, this mechanism opens a discriminatory time window for coincidence detection that enables selective facilitation of Ca2+ influx by appropriately timed low-level receptor stimulation. At higher concentrations, InsP4 acts as an inhibitor of InsP3 receptors, enabling InsP4 to act as a potent bi-modal regulator of cellular sensitivity to InsP3, which provides both facilitatory and inhibitory feedback on Ca2+ signalling.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: InsP4 facilitates InsP3-dependent activation of ICRAC.
Figure 2: Quantitative analysis of InsP4-induced facilitation of ICRAC.
Figure 3: InsP4 and related compounds inhibit 5-phosphatase and InsP3 receptor binding.
Figure 4: InsP4 does not facilitate non-metabolizable Ins(2,4,5)P3.
Figure 5: InsP4 selectively facilitates Ca2+ influx.

Similar content being viewed by others

References

  1. Parekh, A. B. & Penner, R. Store depletion and calcium influx. Physiol. Rev. 77, 901–930 (1997).

    Article  CAS  Google Scholar 

  2. 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 

  3. Irvine, R. F. & Moor, R. M. Micro-injection of inositol 1,3,4,5-tetrakisphosphate activates sea urchin eggs by a mechanism dependent on external Ca2+. Biochem. J. 240, 917–920 (1986).

    Article  CAS  Google Scholar 

  4. 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  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. 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+ mobilization in freshly isolated and cultured mouse lacrimal acinar cells. Biochem. J. 347, 77–82 (2000).

    Article  CAS  Google Scholar 

  7. Fukuda, M. & Mikoshiba, K. The function of inositol high polyphosphate binding proteins. BioEssays 19, 593–603 (1997).

    Article  CAS  Google Scholar 

  8. Cullen, P. J. Bridging the GAP in inositol 1,3,4,5-tetrakisphosphate signalling. Biochim. Biophys. Acta 1436, 35–47 (1998).

    Article  CAS  Google Scholar 

  9. Hoth, M. & Penner, R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355, 353–356 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Parekh, A. B., Fleig, A. & Penner, R. The store-operated calcium current ICRAC: nonlinear activation by InsP3 and dissociation from calcium release. Cell 89, 973–980 (1997).

    Article  CAS  Google Scholar 

  11. Broad, L. M., Armstrong, D. L. & Putney, J. W. Role of the inositol 1,4,5-trisphosphate receptor in Ca2+ feedback Inhibition of calcium release-activated calcium current ICRAC. J. Biol. Chem. 274, 32881–32888 (1999).

    Article  CAS  Google Scholar 

  12. Glitsch, M. D. & Parekh, A. B. Ca2+ store dynamics determines the pattern of activation of the store-operated Ca2+ current ICRAC in response to InsP3 in rat basophilic leukaemia cells. J. Physiol. (Lond.) 523, 283–290 (2000).

    Article  CAS  Google Scholar 

  13. Jones, S. V., Choi, O. H. & Beaven, M. A. Carbachol induces secretion in a mast cell line (RBL-2H3) transfected with the M1 muscarinic receptor gene. FEBS Lett. 289, 47–50 (1991).

    Article  CAS  Google Scholar 

  14. Lewis, R. S. & Cahalan, M. D. Potassium and calcium channels in lymphocytes. Annu. Rev. Immunol. 13, 623–653 (1995).

    Article  CAS  Google Scholar 

  15. Hirata, M. et al. Inositol 1,4,5-trisphosphate receptor subtypes differentially recognize regioisomers of D-myo-inositol 1,4,5-trisphosphate. Biochem. J. 328, 93–98 (1997).

    Article  CAS  Google Scholar 

  16. Guillemette, G., Favreau, I., Lamontagne, S. & Boulay, G. 2,3-Diphosphoglycerate is a nonselective inhibitor of inositol 1,4,5-trisphosphate action and metabolism. Eur. J. Pharmacol. 188, 251–260 (1990).

    Article  CAS  Google Scholar 

  17. Safrany, S. T. et al. Design of potent and selective inhibitors of myo-inositol 1,4,5-trisphosphate 5-phosphatase. Biochemistry 33, 10763–10769 (1994).

    Article  CAS  Google Scholar 

  18. Wojcikiewicz, R. J. Type I, II, and III inositol 1,4,5-trisphosphate receptors are unequally susceptible to down-regulation and are expressed in markedly different proportions in different cell types. J. Biol. Chem. 270, 11678–11683 (1995).

    Article  CAS  Google Scholar 

  19. De Smedt, H. et al. Determination of relative amounts of inositol trisphosphate receptor mRNA isoforms by ratio polymerase chain reaction. J. Biol. Chem. 269, 21691–21698 (1994).

    CAS  PubMed  Google Scholar 

  20. 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  Google Scholar 

  21. 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  Google Scholar 

  22. De Smedt, F. et al. Isoprenylated human brain type I inositol 1,4,5-trisphosphate 5- phosphatase controls Ca2+ oscillations induced by ATP in Chinese hamster ovary cells. J. Biol. Chem. 272, 17367–17375 (1997).

    Article  CAS  Google Scholar 

  23. Parekh, A. B. & Penner, R. Depletion-activated calcium current is inhibited by protein kinase in RBL-2H3 cells. Proc. Natl Acad. Sci. USA 92, 7907–7911 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Hughes, A. R., Takemura, H. & Putney, J. W. 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, 10314–10319 (1988).

    CAS  PubMed  Google Scholar 

  25. da Silva, C. P., Emmrich, F. & Guse, A. H. Adriamycin inhibits inositol 1,4,5-trisphosphate 3-kinase activity in vitro and blocks formation of inositol 1,3,4,5-tetrakisphosphate in stimulated Jurkat T-lymphocytes. Does inositol 1,3,4,5-tetrakisphosphate play a role in Ca2+-entry? J. Biol. Chem. 269, 12521–12526 (1994).

    CAS  PubMed  Google Scholar 

  26. Balla, T. et al. Agonist-induced calcium signaling is impaired in fibroblasts overproducing inositol 1,3,4,5-tetrakisphosphate. J. Biol. Chem. 266, 24719–24726 (1991).

    CAS  PubMed  Google Scholar 

  27. Riley, A. M., Mahon, M. F. & Potter, B. V. L. Rapid synthesis of the enantiomers of myo-inositol 1,3,4,5-tetrakisphosphate by direct chiral desymmetrization of myo-inositol orthoformate. Angew. Chem. Int. Edn. Eng. 36, 1472–1474 (1997).

    Article  CAS  Google Scholar 

  28. Yoshimura, K., Watanabe, Y., Erneux, C. & Hirata, M. Use of phosphorofluoridate analogues of D-myo-inositol 1,4,5-trisphosphate to assess the involvement of ionic interactions in its recognition by the receptor and metabolising enzymes. Cell. Signal. 11, 117–125 (1999).

    Article  CAS  Google Scholar 

  29. Worley, P. F., Baraban, J. M., Supattapone, S., Wilson, V. S. & Snyder, S. H. Characterization of inositol trisphosphate receptor binding in brain. Regulation by pH and calcium. J. Biol. Chem. 262, 12132–12136 (1987).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank D. Tani and M. Monteilh-Zoller for technical assistance; C. Erneux for the InsP3 5-phosphatase plasmid ECH10; the Wellcome Trust for Programme Grant Support (to B.V.L.P.). We acknowledge grant support by the Ministry of Education, Science, Sports and Culture of Japan (to H.T. and M.H.), Kyushu University Interdisciplinary Programs in Education and Projects in Research Development (to M.H.) and The Naito Foundation (to M.H.).

Author information

Authors and Affiliations

  1. Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine at The University of Hawaii, Honolulu, 96813, Hawaii, USA

    Meredith C. Hermosura, Andrea Fleig & Reinhold Penner

  2. Laboratory of Molecular and Cellular Biochemistry, Graduate School of Dental Sciences, Kyushu University and Kyushu University Station for Collaborative Research, Fukuoka, 812-8582, Japan

    Hiroshi Takeuchi & Masato Hirata

  3. Department of Pharmacy & Pharmacology, Wolfson Laboratory of Medicinal Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK

    Andrew M. Riley & Barry V. L. Potter

Authors
  1. Meredith C. Hermosura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Fleig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew M. Riley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barry V. L. Potter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masato Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reinhold Penner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinhold Penner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hermosura, M., Takeuchi, H., Fleig, A. et al. InsP4 facilitates store-operated calcium influx by inhibition of InsP3 5-phosphatase. Nature 408, 735–740 (2000). https://doi.org/10.1038/35047115

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35047115

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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