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J. Biol. Chem., Vol. 276, Issue 20, 17213-17220, May 18, 2001

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p110 and p110 Phosphatidylinositol 3-Kinases Up-regulate FcRI-activated Ca²⁺ Influx by Enhancing Inositol 1,4,5-Trisphosphate Production^*

Alexander J. Smith, Zurab Surviladze, Elizabeth A. Gaudet, Jonathon M. Backer^§, Christina A. Mitchell^¶, and Bridget S. Wilson

From the  Department of Pathology and Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, New Mexico, 87107, ^§ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, and ^¶ Department of Biochemistry and Molecular Biology, Monash University, Clayton 3168, Victoria, Australia

FcRI-induced Ca²⁺ signaling in mast cells is initiated by activation of cytosolic tyrosine kinases. Here, in vitro phospholipase assays establish that the phosphatidylinositol 3-kinase (PI 3-kinase) lipid product, phosphatidylinositol 3,4,5-triphosphate, further stimulates phospholipase C2 that has been activated by conformational changes associated with tyrosine phosphorylation or low pH. A microinjection approach is used to directly assess the consequences of inhibiting class IA PI 3-kinases on Ca²⁺ responses after FcRI cross-linking in RBL-2H3 cells. Injection of antibodies to the p110 or p110 catalytic isoforms of PI 3-kinase, but not antibodies to p110, lengthens the lag time to release of Ca²⁺ stores and blunts the sustained phase of the calcium response. Ca²⁺ responses are also inhibited in cells microinjected with recombinant inositol polyphosphate 5-phosphatase I, which degrades inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃), or heparin, a competitive inhibitor of the Ins(1,4,5)P₃ receptor. This indicates a requirement for Ins(1,4,5)P₃ to initiate and sustain Ca²⁺ responses even when PI 3-kinase is fully active. Antigen-induced cell ruffling, a calcium-independent event, is blocked by injection of p110 and p110 antibodies, but not by injection of 5-phosphatase I, heparin, or anti-p110 antibodies. These results suggest that the p110 and p110 isoforms of PI 3-kinase support FcRI-induced calcium signaling by modulating Ins(1,4,5)P₃ production, not by directly regulating the Ca²⁺ influx channel.

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