Summary
We have previously shown that PIP5KIβ and PIP5KIγ generate functionally distinct pools of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] important for antigen-stimulated Ca2+ entry in mast cells. In the present study, we find that association of the endoplasmic reticulum (ER) Ca2+ sensor, STIM1, and the store-operated Ca2+ 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)P2 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)P2 in the DRM fraction and inhibits thapsigargin-stimulated STIM1–Orai1 association and store-operated Ca2+ entry, whereas the inositol 5-phosphatase S15-Inp54p, which is targeted to disordered lipids, decreases PtdIns(4,5)P2 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)P2 in the distinctive membrane domains. Our results are consistent with a model of PtdIns(4,5)P2 balance, in which store-depletion-stimulated STIM1–Orai1 association is positively regulated by the ordered lipid pool of PtdIns(4,5)P2 and negatively regulated by PtdIns(4,5)P2 in disordered lipid domains.
- Accepted April 13, 2011.
- © 2011.
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