Novel function of phosphoinositide 3-kinase in T cell Ca2+ signaling: A phosphatidylinositol 3,4,5-trisphosphate-mediated Ca2+ entry mechanism

Ao Lin Hsu, Tsui Ting Ching, Goutam Sen, Da Sheng Wang, Subbarao Bondada, Kalwant S. Authi, Ching Shih Chen

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56 Scopus citations

Abstract

This study presents evidence that phosphoinositide (PI) 3-kinase is involved in T cell Ca2+ signaling via a phosphatidylinositol 3,4,5- trisphosphate PI(3,4,5)P3-sensitive Ca2+ entry pathway. First, exogenous PI(3,4,5)P3 at concentrations close to its physiological levels induces Ca2+ influx in T cells, whereas PI(3,4)P(v) PI(4,5)P2, and PI(3)P have no effect on [Ca2+](i). This Ca2+ entry mechanism is cell type-specific as B cells and a number of cell lines examined do not respond to PI(3,4,5)P3 stimulation. Second, inhibition of PI 3-kinase by wortmannin and by overexpression of the dominant negative inhibitor Δp85 suppresses anti-CD3- induced Ca2+ response, which could be reversed by subsequent exposure to PI(3,4,5)P3. Third, PI(3,4,5)P3 is capable of stimulating Ca2+ efflux from Ca2+-loaded plasma membrane vesicles prepared from Jurkat T cells, suggesting that PI(3,4,5)P3 interacts with a Ca2+ entry system directly or via a membrane-bound protein. Fourth, although D-myo-inositol 1,3,4,5- tetrakisphosphate (Ins(1,3,4,5)P4) mimics PI(3,4,5)P3 in many aspects of biochemical functions such as membrane binding and Ca2+ transport, we raise evidence that Ins(1,3,4,5)P4 does not play a role in anti-CD3- or PI(3,4,5)P3-mediated Ca2+ entry. This PI(3,4,5)P3-stimulated Ca2+ influx connotes physiological significance, considering the pivotal role of PI 3-kinase in the regulation of T cell function. Given that PI 3-kinase and phospholipase C-γ form multifunctional complexes downstream of many receptor signaling pathways, we hypothesize that PI(3,4,5)P3-induced Ca2+ entry acts concertedly with Ins(1,4,5)P3-induced Ca2+ release in initiating T cell Ca2+ signaling. By using a biotinylated analog of PI(3,4,5)P3 as the affinity probe, we have detected several putative PI(3,4,5)P3-binding proteins in T cell plasma membranes.

Original languageEnglish
Pages (from-to)16242-16250
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number21
DOIs
StatePublished - May 26 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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