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Ion Channels Modulating Mouse Dendritic Cell Functions¹

Nicole Matzner^*, Irina M. Zemtsova^*, Nguyen Thi Xuan^*, Michael Duszenko, Ekaterina Shumilina^2,3,* and Florian Lang^2,*

^* Department of Physiology, University of Tübingen, Gmelinstr. 5, Tübingen, Germany; and Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, Tübingen, Germany

Ca²⁺-mediated signal transduction pathways play a central regulatory role in dendritic cell (DC) responses to diverse Ags. However, the mechanisms leading to increased [Ca²⁺]_i upon DC activation remained ill-defined. In the present study, LPS treatment (100 ng/ml) of mouse DCs resulted in a rapid increase in [Ca²⁺]_i, which was due to Ca²⁺ release from intracellular stores and influx of extracellular Ca²⁺ across the cell membrane. In whole-cell voltage-clamp experiments, LPS-induced currents exhibited properties similar to the currents through the Ca²⁺ release-activated Ca²⁺ channels (CRAC). These currents were highly selective for Ca²⁺, exhibited a prominent inward rectification of the current-voltage relationship, and showed an anomalous mole fraction and a fast Ca²⁺-dependent inactivation. In addition, the LPS-induced increase of [Ca²⁺]_i was sensitive to margatoxin and ICAGEN-4, both inhibitors of voltage-gated K⁺ (Kv) channels Kv1.3 and Kv1.5, respectively. MHC class II expression, CCL21-dependent migration, and TNF- and IL-6 production decreased, whereas phagocytic capacity increased in LPS-stimulated DCs in the presence of both Kv channel inhibitors as well as the I_CRAC inhibitor SKF-96365. Taken together, our results demonstrate that Ca²⁺ influx in LPS-stimulated DCs occurs via Ca²⁺ release-activated Ca²⁺ channels, is sensitive to Kv channel activity, and is in turn critically important for DC maturation and functions.

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 This work was supported by by the Deutsche Forschungsgemeinschaft DFG (SFB 766) and The International Graduate School (GRK 1302/1) "The PI3K Pathway in Tumor Growth and Diabetes".

² These authors share last authorship.

³ Address correspondence and reprint requests to Dr. Ekaterina Shumilina, Department of Physiology, University of Tübingen, Gmelinstr. 5, Tübingen, Germany. E-mail address: ekaterina.shumilina{at}uni-tuebingen.de

⁴ Abbreviations used in this paper: DC, dendritic cell; CamK, Calmodulin kinase; CRAC, Ca²⁺ release-activated Ca²⁺ channel; Kv, voltage-gated K⁺; MgTx, margatoxin.