Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides

Marek K. Korzeniowski, Marko A. Popovic, Zsofia Szentpetery, Peter Varnai, Stanko S. Stojilkovic, Tomas Balla

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Recent studies identified two main components of store-operated calcium entry (SOCE): the endoplasmic reticulum-localized Ca2+ sensor protein, STIM1, and the plasma membrane (PM)-localized Ca2+ channel, Orai1/CRACM1. In the present study, we investigated the phosphoinositide dependence of Orai1 channel activation in the PM and of STIM1 movements from the tubular to PM-adjacent endoplasmic reticulum regions during Ca2+ store depletion. Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) levels were changed either with agonist stimulation or by chemically induced recruitment of a phosphoinositide 5-phosphatase domain to the PM, whereas PtdIns4P levels were decreased by inhibition or down-regulation of phosphatidylinositol 4-kinases (PI4Ks). Agonist-induced phospholipase C activation and PI4K inhibition, but not isolated PtdIns(4,5)P2 depletion, substantially reduced endogenous or STIM1/Orai1-mediated SOCE without preventing STIM1 movements toward the PM upon Ca2+ store depletion. Patch clamp analysis of cells overexpressing STIM1 and Orai1 proteins confirmed that phospholipase C activation or PI4K inhibition greatly reduced ICRAC currents. These results suggest an inositide requirement of Orai1 activation but not STIM1 movement and indicate that PtfIns4P rather than PtdIns(4,5)P2 is a likely determinant of Orai1 channel activity.

Original languageEnglish
Pages (from-to)21027-21035
Number of pages9
JournalJournal of Biological Chemistry
Issue number31
Publication statusPublished - Jul 31 2009


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Korzeniowski, M. K., Popovic, M. A., Szentpetery, Z., Varnai, P., Stojilkovic, S. S., & Balla, T. (2009). Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. Journal of Biological Chemistry, 284(31), 21027-21035.