The voltage-gated potassium channel K_V1.3 regulates neutrophil recruitment during inflammation

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_V1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca²⁺ signalling.

Using in vitro assays and electrophysiological techniques, we show that K_V1.3 is functionally expressed in human neutrophils regulating sustained store-operated Ca²⁺ entry through membrane potential stabilizing K⁺ efflux. Inhibition of K_V1.3 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_V1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified K_V1.3 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_V1.3.

We show that the voltage-gated potassium channel K_V1.3 is critical for Ca²⁺ signalling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of K_V1.3 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.