Inwardly rectifying potassium channels regulate direction sensing during neutrophil chemotaxis

Abstract
Potassium channels regulate membrane potential and diverse physiological processes, including cell migration. However, the specific function of the inwardly rectifying potassium channels in immune cell chemotaxis is unknown. Here, we identified that the inwardly rectifying potassium channel Kir7.1 (KCNJ13) maintains the resting membrane potential and is required for directional sensing during neutrophil chemotaxis. Pharmacological or genetic inhibition of Kir7.1 in neutrophils impaired direction sensing toward various chemoattractants without affecting cell polarization in multiple neutrophil models. Using genetically encoded voltage indicators, we observed oscillating hyperpolarization of the membrane potential for tail retraction in zebrafish neutrophils, and Kir7.1 is required for polarized depolarization towards the chemokine source. Focal depolarization with optogenetic tools biases pseudopod selection and induces de novo protrusions. Global hyperpolarizing neutrophils stalled cell migration. Furthermore, Kir7.1 regulates GPCR signaling activation. This work adds membrane potential to the intricate feedforward mechanism, coupling the adaptive and excitable network required to steer immune cells in complex tissue environments.

Keywords: Kir7.1, bioelectricity, direction sensing, zebrafish, neutrophil

Contributing Authors:
Dr. Tianqi Wang, Mr. Daniel H Kim, Ms. Chang Ding, Mr. Dingxun Wang, Dr. Weiwei Zhang, Dr. Martin Silic, Dr. Xi Cheng, Mr. Kunming Shao, Mr. TingHsuan Ku, Mr. Conwy Zheng, Dr. Junkai Xie, Dr. Chongli Yuan, Dr. Alexander A Chubykin, Prof. Christopher J Staiger, Dr. Guangjun Zhang