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 γ (PIP5KIγ87) as the major contributor of the PIP₂ pool that supports G protein–coupled receptor (GPCR)-mediated IP₃ generation. PIP5KIγ87 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, PIP5KIγ87's PIP₂ pool that supports GPCR-mediated Ca²⁺ signaling is functionally compartmentalized from those generated by the other PIP5KIs.