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Molecular and Cellular Biology, August 2006, p. 5595-5602, Vol. 26, No. 15
0270-7306/06/$08.00+0 doi:10.1128/MCB.00352-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Departments of Pharmacology,1 Pediatric Cardiology,2 Division of Nephrology,3 The Skirball Institute, New York University School of Medicine, New York, New York,4 Vanderbilt University Medical School, Department of Microbiology and Immunology, Nashville, Tennessee5
Received 27 February 2006/ Returned for modification 28 March 2006/ Accepted 9 May 2006
Intracellular Ca2+ levels rapidly rise following cross-linking of the T-cell receptor (TCR) and function as a critical intracellular second messenger in T-cell activation. It has been relatively under appreciated that K+ channels play an important role in Ca2+ influx into T lymphocytes by helping to maintain a negative membrane potential which provides an electrochemical gradient to drive Ca2+ influx. Here we show that the Ca2+-activated K+ channel, KCa3.1, which is critical for Ca2+ influx in reactivated naive T cells and central memory T cells, requires phosphatidylinositol-3 phosphatase [PI(3)P] for activation and is inhibited by the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6). Moreover, by inhibiting KCa3.1, MTMR6 functions as a negative regulator of Ca2+ influx and proliferation of reactivated human CD4 T cells. These findings point to a new and unexpected role for PI(3)P and the PI(3)P phosphatase MTMR6 in the regulation of Ca2+ influx in activated CD4 T cells and suggest that MTMR6 plays a critical role in setting a minimum threshold for a stimulus to activate a T cell.
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