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J. Biol. Chem., Vol. 283, Issue 21, 14559-14570, May 23, 2008

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TWIK-related Acid-sensitive K⁺ Channel 1 (TASK1) and TASK3 Critically Influence T Lymphocyte Effector Functions^*

Sven G. Meuth¹², Stefan Bittner¹³, Patrick Meuth, Ole J. Simon, Thomas Budde^¶, and Heinz Wiendl

From the Department of Neurology, University of Wuerzburg, Josef-Schneider-Str. 11, 97080 Wuerzburg, the ^¶Westfaelische Wilhelms-University Muenster, Institute for Experimental Epilepsy Research, Huefferstr. 68, 48149 Muenster, Germany, and the Westfaelische Wilhelms-University Muenster, Institute of Physiology I, Robert-Koch-Str. 27a, 48149 Muenster, Germany

Two major K⁺ channels are expressed in T cells, (i) the voltage-dependent K_V1.3 channel and (ii) the Ca²⁺-activated K⁺ channel KCa 3.1 (IKCa channel). Both critically influence T cell effector functions in vitro and animal models in vivo. Here we identify and characterize TWIK-related acid-sensitive potassium channel 1 (TASK1) and TASK3 as an important third K⁺ conductance on T lymphocytes. T lymphocytes constitutively express TASK1 and -3 protein. Application of semi-selective TASK blockers resulted in a significant reduction of cytokine production and cell proliferation. Interference with TASK channels on CD3⁺ T cells revealed a dose-dependent reduction (40%) of an outward current in patch clamp recordings indicative of TASK channels, a finding confirmed by computational modeling. In vivo relevance of our findings was addressed in an experimental model of multiple sclerosis, adoptive transfer experimental autoimmune encephalomyelitis. Pretreatment of myelin basic protein-specific encephalitogenic T lymphocytes with TASK modulators was associated with significant amelioration of the disease course in Lewis rats. These data introduce K₂P channels as novel potassium conductance on T lymphocytes critically influencing T cell effector function and identify a possible molecular target for immunomodulation in T cell-mediated autoimmune disorders.

Received for publication, January 24, 2008 , and in revised form, March 6, 2008.

^* This work was supported by Interdisciplinary Clinical Research Center (IZKF) Wuerzburg N39-1 (to S. G. M. and H. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally.

³ Submitted in partial fulfillment of a doctoral thesis, Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.

² To whom correspondence should be addressed. Tel.: 49-931-201-23756; Fax: 49-931-201-23488; E-mail: meuth_s{at}klinik.uni-wuerzburg.de.

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