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Ca2+ Influx through Store-operated Calcium Channels Replenishes the Functional Phosphatidylinositol 4,5-Bisphosphate Pool Used by Cysteinyl Leukotriene Type I Receptors*

Abdullah Alswied,A. Parekh

Published 2015 in Journal of Biological Chemistry

ABSTRACT

Background: Phosphatidylinositol 4,5-bisphosphate levels need to be replenished during calcium signaling, but how this is achieved is unclear. Results: Ca2+ entry through Orai1 channels contributes to the resynthesis of phosphatidylinositol 4,5-bisphosphate and, thereby, helps sustain cytoplasmic Ca2+ oscillations. Conclusion: Ca2+ influx sustains cytoplasmic Ca2+ oscillations by regulating phosphatidylinositol-4-phosphate 5-kinase. Significance: Store-operated Ca2+ influx is important in maintaining phosphatidylinositol 4,5-bisphosphate levels. Oscillations in cytoplasmic Ca2+ concentration are a universal mode of signaling following physiological levels of stimulation with agonists that engage the phospholipase C pathway. Sustained cytoplasmic Ca2+ oscillations require replenishment of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), the source of the Ca2+-releasing second messenger inositol trisphosphate. Here we show that cytoplasmic Ca2+ oscillations induced by cysteinyl leukotriene type I receptor activation run down when cells are pretreated with Li+, an inhibitor of inositol monophosphatases that prevents PIP2 resynthesis. In Li+-treated cells, cytoplasmic Ca2+ signals evoked by an agonist were rescued by addition of exogenous inositol or phosphatidylinositol 4-phosphate (PI4P). Knockdown of the phosphatidylinositol 4-phosphate 5 (PIP5) kinases α and γ resulted in rapid loss of the intracellular Ca2+ oscillations and also prevented rescue by PI4P. Knockdown of talin1, a protein that helps regulate PIP5 kinases, accelerated rundown of cytoplasmic Ca2+ oscillations, and these could not be rescued by inositol or PI4P. In Li+-treated cells, recovery of the cytoplasmic Ca2+ oscillations in the presence of inositol or PI4P was suppressed when Ca2+ influx through store-operated Ca2+ channels was inhibited. After rundown of the Ca2+ signals following leukotriene receptor activation, stimulation of P2Y receptors evoked prominent inositol trisphosphate-dependent Ca2+ release. Therefore, leukotriene and P2Y receptors utilize distinct membrane PIP2 pools. Our findings show that store-operated Ca2+ entry is needed to sustain cytoplasmic Ca2+ signaling following leukotriene receptor activation both by refilling the Ca2+ stores and by helping to replenish the PIP2 pool accessible to leukotriene receptors, ostensibly through control of PIP5 kinase activity.

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