K⁺ Channels in Membrane Potential Dynamics and Migration of Neutrophil Granulocytes

Neutrophil granulocytes exhibit dynamic changes in membrane potential upon stimulation with the complement component C5a. It is not well-defined which ion channels are responsible for membrane potential dynamics in neutrophils, although ion channel signaling has been linked to neutrophil behavior. Here, we investigated the contribution of K⁺ channels that are important players in different immune cells: K_Ca3.1, K_ir2.1, and K_V1.3. We studied their roles in membrane potential regulation, chemotaxis, and LTB4 secretion using live-cell imaging, analytical methods, and mathematical modeling. We identify membrane potential dynamics as an important regulatory axis in neutrophil migration. K_ir2.1 is a key regulator of resting membrane potential. K_ir2.1 blockade depolarizes the membrane potential of neutrophils by ~30 mV to -41.9 mV, and it delays and attenuates the C5a-induced depolarization. In contrast, K_Ca3.1 and K_V1.3 inhibition neither modifies the resting membrane potential nor the C5a-induced depolarization. Nonetheless, the inhibition of all three K⁺ channels impairs chemotaxis toward C5a, in part by a reduced LTB₄ secretion and/or possibly by non-conductive properties related to the interactome of the three K⁺ channels. Together, these findings demonstrate that K_Ca3.1, K_V1.3 and K_ir2.1 channels play distinct but critical roles in neutrophil function and inflammatory signalling.