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Immler, Roland; Nadolni, Wiebke; Bertsch, Annika; Morikis, Vasilios; Rohwedder, Ina; Masgrau-Alsina, Sergi; Schroll, Tobias; Yevtushenko, Anna; Soehnlein, Oliver; Moser, Markus; Gudermann, Thomas; Barnea, Eytan R.; Rehberg, Markus; Simon, Scott I.; Zierler, Susanna; Pruenster, Monika and Sperandio, Markus (2021): The voltage-gated potassium channel K(V)1.3 regulates neutrophil recruitment during inflammation. In: Cardiovascular Research, Vol. 118, No. 5: pp. 1289-1302

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Aims Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signalling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel K(V)1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signalling. Methods and results Using in vitro assays and electrophysiological techniques, we show that K(V)1.3 is functionally expressed in human neutrophils regulating sustained store-operated Ca2+ entry through membrane potential stabilizing K+ efflux. Inhibition of K(V)1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signalling, thereby preventing cellular spreading, adhesion strengthening, and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of K(V)1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified K(V)1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of Escherichia coli particles by neutrophils in the absence of K(V)1.3. Conclusion We show that the voltage-gated potassium channel K(V)1.3 is critical for Ca2+ signalling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of K(V)1.3 for sustained calcium signalling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration.

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