Critical role of PIP5KIγ87 in InsP3-mediated Ca2+ signaling

Phosphatidylinositol 4,5-bisphosphate (PIP2) is the obligatory precursor of inositol 1,4,5-trisphosphate (InSP3 or IP3) and is therefore critical to intracellular Ca2+ signaling. Using RNA interference (RNAi), we identified the short splice variant of type I phosphatidylinositol 4-phosphate 5-kinase gamma (PIP5KIgamma87) as the major contributor of the PIP2 Pool that supports G protein-coupled receptor (GPCR)-mediated IP3 generation. PIP5KIgamma87 RNAi decreases the histamine-induced IP3 response and Ca2+ flux by 70%. Strikingly, RNAi of other PIP5KI isoforms has minimal effect, even though some of these isoforms account for a larger percent of total PIP2 mass and have previously been implicated in receptor mediated endocytosis or focal adhesion formation. Therefore, PIP5KIgamma87's PIP2 pool that supports GPCR-mediated Ca2+ signaling is functionally compartmentalized from those generated by the other PIP5KIs.