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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.

Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells

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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This article has been cited by other articles:

• Harris, S. J., Parry, R. V., Westwick, J., Ward, S. G. (2008). Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes. J. Biol. Chem. 283: 2465-2469 [Abstract] [Full Text]  
• Choudhury, P., Srivastava, S., Li, Z., Ko, K., Albaqumi, M., Narayan, K., Coetzee, W. A., Lemmon, M. A., Skolnik, E. Y. (2006). Specificity of the Myotubularin Family of Phosphatidylinositol-3-phosphatase Is Determined by the PH/GRAM Domain. J. Biol. Chem. 281: 31762-31769 [Abstract] [Full Text]