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J Cell Sci. 2011 Aug 1;124(Pt 15):2602-10. doi: 10.1242/jcs.084178. Epub 2011 Jul 12.

Stimulated association of STIM1 and Orai1 is regulated by the balance of PtdIns(4,5)P₂ between distinct membrane pools.

Author information

1
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.

Abstract

We have previously shown that PIP5KIβ and PIP5KIγ generate functionally distinct pools of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2)] important for antigen-stimulated Ca(2+) entry in mast cells. In the present study, we find that association of the endoplasmic reticulum (ER) Ca(2+) sensor, STIM1, and the store-operated Ca(2+) channel, Orai1, stimulated by thapsigargin-mediated ER store depletion, is enhanced by overexpression of PIP5KIβ and inhibited by overexpression of PIP5KIγ. These different PIP5KI isoforms cause differential enhancement of PtdIns(4,5)P(2) in detergent-resistant membrane (DRM) fractions, which comprise ordered lipid regions, and detergent-solubilized membrane (DSM) fractions, which comprise disordered lipid regions. Consistent with these results, the inositol 5-phosphatase L10-Inp54p, which is targeted to ordered lipids, decreases PtdIns(4,5)P(2) in the DRM fraction and inhibits thapsigargin-stimulated STIM1-Orai1 association and store-operated Ca(2+) entry, whereas the inositol 5-phosphatase S15-Inp54p, which is targeted to disordered lipids, decreases PtdIns(4,5)P(2) in the DSM fraction and enhances STIM1-Orai1 association. Removal of either the STIM1 C-terminal polylysine sequence (amino acids 677-685) or an N-terminal polyarginine sequence in Orai1 (amino acids 28-33) eliminates this differential sensitivity of STIM1-Orai1 association to PtdIns(4,5)P(2) in the distinctive membrane domains. Our results are consistent with a model of PtdIns(4,5)P(2) balance, in which store-depletion-stimulated STIM1-Orai1 association is positively regulated by the ordered lipid pool of PtdIns(4,5)P(2) and negatively regulated by PtdIns(4,5)P(2) in disordered lipid domains.

PMID:
21750194
PMCID:
PMC3138702
DOI:
10.1242/jcs.084178
[Indexed for MEDLINE]
Free PMC Article

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