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J. Biol. Chem., Vol. 279, Issue 40, 41444-41452, October 1, 2004

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Plasmodium Induces Swelling-activated ClC-2 Anion Channels in the Host Erythrocyte^*

Stephan M. Huber, Christophe Duranton, Guido Henke, Claudia van de Sand¶, Volker Heussler¶, Ekaterina Shumilina, Ciprian D. Sandu, Valerie Tanneur, Verena Brand, Ravi S. Kasinathan, Karl S. Lang, Peter G. Kremsner||, Christian A. Hübner**, Marco B. Rust**, Karin Dedek**, Thomas J. Jentsch**, and Florian Lang

From the Departments of Physiology and ^||Parasitology, Institute of Tropical Medicine, University of Tübingen, 72076 Germany, the ^¶Bernhard Nocht Institute and the ^**Center for Molecular Neurobiology, University of Hamburg, 20359 and 20251 Germany, and the Department of Neurobiology, University of Oldenburg, 26111 Germany

Intraerythrocytic growth of the human malaria parasite Plasmodium falciparum depends on delivery of nutrients. Moreover, infection challenges cell volume constancy of the host erythrocyte requiring enhanced activity of cell volume regulatory mechanisms. Patch clamp recording demonstrated inwardly and outwardly rectifying anion channels in infected but not in control erythrocytes. The molecular identity of those channels remained elusive. We show here for one channel type that voltage dependence, cell volume sensitivity, and activation by oxidation are identical to ClC-2. Moreover, Western blots and FACS analysis showed protein and functional ClC-2 expression in human erythrocytes and erythrocytes from wild type (Clcn2^+/+) but not from Clcn2^–/– mice. Finally, patch clamp recording revealed activation of volume-sensitive inwardly rectifying channels in Plasmodium berghei-infected Clcn2^+/+ but not Clcn2^–/– erythrocytes. Erythrocytes from infected mice of both genotypes differed in cell volume and inhibition of ClC-2 by ZnCl₂ (1 mM) induced an increase of cell volume only in parasitized Clcn2^+/+ erythrocytes. Lack of ClC-2 did not inhibit P. berghei development in vivo nor substantially affect the mortality of infected mice. In conclusion, activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival.

Received for publication, July 7, 2004 , and in revised form, July 21, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft (DFG, La 315/11-1 and -2), by the Forschungsschwerpunktprogrammes des Landes Baden-Württemberg Dynamik und Modulation zellulärer Infektionsprozesse, by the fortüne program (838-1-1) of the University of Tübingen, by a grant from the Alexander von Humboldt foundation (to C. D. and E. S.), and by a Marie Curie fellowship (to C. S.). 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.

To whom correspondence should be addressed: Dept. of Physiology I, Eberhard-Karls-University Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany. Tel.: 49-7071-29-76737; Fax: 49-7071-29-3073; E-mail: stephan.huber{at}uni-tuebingen.de.

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