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MBC in Press, published online ahead of print July 8, 2009
Mol. Biol. Cell 10.1091/mbc.E09-05-0390

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Submitted on May 13, 2009
Revised on June 19, 2009
Accepted on June 30, 2009

The Class II Phosphatidylinositol 3 kinase C2 Beta Is Required for the Activation of the K+ Channel KCa3.1 and CD4 T-Cells

Shekhar Srivastava,*{dagger} Lie Di,*{dagger} Olga Zhdanova,{dagger}{ddagger} Zhai Li,*{dagger} Santosha Vardhana,{dagger}{sect} Qi Wan,{dagger}{sect} Ying Yan,|| Rajat Varma,¶ Jonathan Backer,|| Heike Wulff,# Michael L. Dustin,{dagger}{sect} and Edward Y. Skolnik*{dagger}{ddagger}

{ddagger}Division of Nephrology, *Departments of Pharmacology and {sect}Molecular Pathogenesis, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the {dagger}Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016; T-Cell Biophysics Unit, National Institue of Allergy and Infectious Diseases, Bethesda, MD 20892; ||Department of Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; #Department of Medical Pharmacology and Toxicology, University of California Davis, Davis, CA 95616

Monitoring Editor: Carl-Henrik Heldin

The Ca2+-activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of T-cells. We previously showed that Nucleoside Diphosphate Kinase Beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. We now show that the class II phosphatidylinositol 3 kinase-C2beta (PI3K-C2{beta}) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. Decreased expression of PI3K-C2{beta} by siRNA in human CD4 T-cells resulted in inhibition of KCa3.1 channel activity. The inhibition was due to decreased PI(3)P because dialyzing PI3K-C2{beta} siRNA treated T-cells with PI(3)P rescued KCa3.1 channel activity. Moreover, overexpression of PI3K-C2{beta} in KCa3.1-transfected Jurkat T-cells led to increased TCR-stimulated activation of KCa3.1 and Ca2+ influx, whereas silencing of PI3K-C2{beta} inhibited both responses. Using total internal reflection fluorescence microscopy (TIRF) and planar lipid bilayers, we found that PI3K-C2{beta} colocalized with Zap70 and the TCR in peripheral microclusters in the immunological synapse. This is the first demonstration that a class II PI3K plays a critical role in T-cell activation.

Address correspondence to: Edward Y. Skolnik (edward.skolnik{at}nyumc.org)






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