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A novel mechanism for the store-operated calcium influx pathway

Nature Cell Biology volume 6, pages 113–120 (2004)Cite this article

Abstract

Activation of store-operated channels (SOCs) and capacitative calcium influx are triggered by depletion of intracellular calcium stores. However, the exact molecular mechanism of such communication remains unclear. Recently, we demonstrated1 that native SOC channels2 can be activated by calcium influx factor (CIF)3 that is produced upon depletion of calcium stores4,5, and showed that Ca2+-independent phospholipase A2 (iPLA2) has an important role in the store-operated calcium influx pathway6. Here, we identify the key plasma-membrane-delimited events that result in activation of SOC channels. We also propose a novel molecular mechanism in which CIF displaces inhibitory calmodulin (CaM) from iPLA2, resulting in activation of iPLA2 and generation of lysophospholipids that in turn activate soc channels and capacitative calcium influx. Upon refilling of the stores and termination of CIF production, CaM rebinds to iPLA2, inhibits it, and the activity of SOC channels and capacitative calcium influx is terminated.

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Figure 1: Correlation between activation of iPLA2 and store-operated calcium influx.
Figure 2: CaM and iPLA2-dependent activation of single SOC channels.
Figure 3: Activation of capacitative calcium influx by lysophospholipids.
Figure 4: Activation of single SOC channels by lysophosphatidylinositol.
Figure 5: A new model for activation of SOC channels by depletion of calcium stores.

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References

  1. Trepakova, E.S., Csutora, P., Marchase, R.B., Cohen, R.A. & Bolotina, V.M. Calcium influx factor (CIF) directly activates store-operated cation channels in vascular smooth muscle cells. J. Biol. Chem. 275, 26158–26163 (2000).

    Article  CAS  Google Scholar 

  2. Trepakova, E.S. et al. Properties of a native cation channel activated by Ca2+ store depletion in vascular smooth muscle cells. J. Biol. Chem. 276, 7782–7790 (2001).

    Article  CAS  Google Scholar 

  3. Randriamampita, C. & Tsien, R.Y. Emptyining of intracellular Ca2+ stores releases a novel small messenger that stimulates Ca2+ influx. Nature 364, 809–814 (1993).

    Article  CAS  Google Scholar 

  4. Kim, H.Y., Thomas, D. & Hanley, M.R. Chromatographic resolution of an intracellular calcium influx factor from thapsigargin-activated Jurkat cells. Evidence for multiple activities influencing calcium elevation in Xenopus oocytes. J. Biol. Chem. 270, 9706–9708 (1995).

    Article  CAS  Google Scholar 

  5. Csutora, P. et al. Calcium influx factor is synthesised by east and mammalian cells depleated of organellar calcium stores. Proc. Natl Acad. Sci. USA 96, 121–126 (1999).

    Article  CAS  Google Scholar 

  6. Smani, T. et al. Ca2+-independent Phospholipase A2 is a novel determinant of store-operated Ca2+ entry. J. Biol. Chem. 278, 11909–11915 (2003).

    Article  CAS  Google Scholar 

  7. Putney, J.W. Jr & Bird, G. St J. The signal for capacitative calcium entry. Cell 75, 199–201 (1993).

    Article  CAS  Google Scholar 

  8. Berridge, M.J. Capacitative calcium entry. Biochem. J. 312, 1–11 (1995).

    Article  CAS  Google Scholar 

  9. Clapham, D.E. Calcium signaling. Cell 80, 259–268 (1995).

    Article  CAS  Google Scholar 

  10. Thomas, D. & Hanley, M.R. Evaluation of calcium influx factors from stimulated Jurkat T- lymphocytes by microinjection into Xenopus oocytes. J. Biol. Chem. 270, 6429–6432 (1995).

    Article  CAS  Google Scholar 

  11. Winstead, M.V., Balsinde, J. & Dennis, E.A. Calcium-independent phospholipase A2: structure and function. Biochem. Biophys. Acta 1488, 28–39 (2000).

    CAS  PubMed  Google Scholar 

  12. Wolf, M.J. & Gross, R.W. The calcium-dependent association and functional coupling of calmodulin with myocardial phospholipase A2 . J. Biol. Chem. 271, 20989–20992 (1996).

    Article  CAS  Google Scholar 

  13. Jenkins, C.M., Wolf, M.J., Mancuso, D.J. & Gross, R.W. Identification of the calmodulin-binding domain of recombinant calcium-independent phospholipase A2β. Implications for structure and function. J. Biol. Chem. 276, 7129–7135 (2001).

    Article  CAS  Google Scholar 

  14. Wolf, M.J., Wang, J., Turk, J. & Gross, R.W. Depletion of intracellular calcium stores activates smooth muscle cell calcium-independent phospholipase A2 . J. Biol. Chem. 272, 1522–1526 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Wolf, M.J. & Gross, R.W. Expression, purification, and kinetic characterization of a recombinant 80-kDa intracellular calcium-independent phospholipase A2. J. Biol. Chem. 271, 30879–30885 (1996).

    Article  CAS  Google Scholar 

  17. Su, Z. et al. Regulation of Ca2+ release-activated Ca2+ channels by INAD and Ca2+ influx factor. Am. J. Physiol. 284, C497–C505 (2003).

    Article  CAS  Google Scholar 

  18. Shuttleworth, T.J. & Thompson, J.L. Discriminating between capacitative and arachidonate-activated Ca2+ entry pathways in HEK293 Cells. J. Biol. Chem. 274, 31174–31178 (1999).

    Article  CAS  Google Scholar 

  19. Osterhout, J.L. & Shuttleworth, T.J. A Ca2+-independent activation of a type IV cytosolic phospholipase A2 underlies the receptor stimulation of arachidonic acid-dependent noncapacitative calcium entry. J. Biol. Chem. 275, 8248–8254 (2000).

    Article  CAS  Google Scholar 

  20. Hamilton, J.A. Fatty acid transport: difficult or easy? J. Lipid Res. 39, 467–481 (1998).

    CAS  PubMed  Google Scholar 

  21. Vaca, L. Calmodulin inhibits calcium influx current in vascular endothelium. FEBS Lett. 390, 289–293 (1996).

    Article  CAS  Google Scholar 

  22. Albert, A.P. & Large, W.A. A Ca2+-permeable non-selective cation channel activated by depletion of internal Ca2+ stores in single rabbit portal vein myocytes. J. Physiol. 538, 717–728 (2002).

    Article  CAS  Google Scholar 

  23. Petersen, C.C.H. & Berridge, M.J. Capacitative calcium entry is colocalised with calcium release in Xenopus oocytes: evidence against a highly diffusable calcium influx factor. Pflugers Arch. 432, 286–292 (1996).

    Article  CAS  Google Scholar 

  24. Jaconi, M., Pyle, J., Bortolon, R., Ou, J. & Clapham, D.E. Calcium release and influx colocalize to the endoplasmic reticulum. Curr. Biol. 7, 599–602 (1997).

    Article  CAS  Google Scholar 

  25. Yao, Y., Ferrer-Montiel, A.V., Montal, M. & Tsien, R.Y. Activation of store-operated Ca2+ current in Xenopus oocytes requires SNAP-25 but not a diffusible messenger. Cell 98, 475–485 (1999).

    Article  CAS  Google Scholar 

  26. Irvine, R.F. 'Quantal' Ca2+ release and the control of Ca2+ entry by inositol phosphates – a possible mechanism. FEBS Lett. 263, 5–9 (1990).

    Article  CAS  Google Scholar 

  27. Chevesich, J., Kreuz, A.J. & Montell, C. Requirement for the PDZ domain protein, INAD, for localization of the TRP store-operated channel to a signaling complex. Neuron 18, 95–105 (1997).

    Article  CAS  Google Scholar 

  28. Lan, L., Brereton, H. & Barritt, G.J. The role of calmodulin-binding sites in the regulation of the Drosophila TRPL cation channel expressed in Xenopus laevis oocytes by Ca2+, inositol 1,4,5-trisphosphate and GTP-binding proteins. Biochem. J. 330, 1149–1158 (1998).

    Article  CAS  Google Scholar 

  29. Tang, J. et al. Identification of common binding sites for calmodulin and inositol 1,4,5-trisphosphate receptors on the carboxyl termini of Trp Channels. J. Biol. Chem. 276, 21303–21310 (2001).

    Article  CAS  Google Scholar 

  30. Zhang, Z. et al. Activation of Trp3 by inositol 1,4,5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain. Proc. Natl Acad. Sci. USA 98, 3168–3173 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank C. Montell, R. Gross, J. Hamilton, C. Taylor and R. Penner for stimulating discussions, and R. Cohen for continued support and valuable help with the manuscript. This study was supported by National Institutes of Health grant HL54150, American Heart Association grant 225688T (to T.S.), and by OTKA grant F038149 (to P.C.).

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Author notes

  1. Tarik Smani and Sergey I. Zakharov: These authors contributed equally to the work.

Authors and Affiliations

  1. Boston University School of Medicine, Boston, 02118, MA, USA

    Tarik Smani, Sergey I. Zakharov, Endri Leno, Elena S. Trepakova & Victoria M. Bolotina

  2. Pecs University, Pecs, 7624, Hungary

    Peter Csutora

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  1. Tarik Smani
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Correspondence to Victoria M. Bolotina.

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Smani, T., Zakharov, S., Csutora, P. et al. A novel mechanism for the store-operated calcium influx pathway. Nat Cell Biol 6, 113–120 (2004). https://doi.org/10.1038/ncb1089

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