Ca2+ influx through store-operated calcium channels replenishes the functional phosphatidylinositol 4,5-bisphosphate pool used by cysteinyl leukotriene type I receptors [Membrane Biology]

October 14th, 2015 by Alswied, A., Parekh, A. B.

Oscillations in cytoplasmic Ca2+ concentration are a universal mode of signalling following physiological levels of stimulation with agonists that engage the phospholipase C pathway. Sustained cytoplasmic Ca2+ oscillations require replenishment of the membrane phospholipid phosphatidylinositol 4,5bisphosphate (PIP2), the source of the Ca2+-releasing second messenger inositol trisphosphate (InsP3). Here we show that cytoplasmic Ca2+ oscillations induced by cysteinyl leukotriene type I receptor activation run down when cells are pre-treated with Li+, an inhibitor of inositol monophosphatases and which prevents PIP2 resynthesis. In Li+-treated cells, cytoplasmic Ca2+ signals evoked by agonist were rescued by addition of exogenous inositol or phosphatidylinositol 4-phosphate (PI4P). Knock down of phosphatidylinositol 4-phosphate 5- kinases (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 InsP3-dependent Ca2+ release. Hence leukotriene and P2Y receptors utilise distinct membrane PIP2 pools. Our findings show that store-operated Ca2+ entry is needed to sustain cytoplasmic Ca2+ signalling 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.
  • Posted in Journal of Biological Chemistry, Publications
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