Regulation of Neutrophil Functions by Hv1/VSOP Voltage-Gated Proton Channels.

Yoshifumi Okochi,Yasushi Okamura

doi:10.3390/ijms22052620

Abstract

The voltage-gated proton channel, Hv1, also termed VSOP, was discovered in 2006. It has long been suggested that proton transport through voltage-gated proton channels regulate reactive oxygen species (ROS) production in phagocytes by counteracting the charge imbalance caused by the activation of NADPH oxidase. Discovery of Hv1/VSOP not only confirmed this process in phagocytes, but also led to the elucidation of novel functions in phagocytes. The compensation of charge by Hv1/VSOP sustains ROS production and is also crucial for promoting Ca2+ influx at the plasma membrane. In addition, proton extrusion into neutrophil phagosomes by Hv1/VSOP is necessary to maintain neutral phagosomal pH for the effective killing of bacteria. Contrary to the function of Hv1/VSOP as a positive regulator for ROS generation, it has been revealed that Hv1/VSOP also acts to inhibit ROS production in neutrophils. Hv1/VSOP inhibits hypochlorous acid production by regulating degranulation, leading to reduced inflammation upon fungal infection, and suppresses the activation of extracellular signal-regulated kinase (ERK) signaling by inhibiting ROS production. Thus, Hv1/VSOP is a two-way player regulating ROS production. Here, we review the functions of Hv1/VSOP in neutrophils and discuss future perspectives.

Highlights

Voltage-gated proton channels are highly proton-selective channels
These results indicate that voltagegated proton channels compensate for charge imbalances caused by the activation of Neutrophils normally circulate in blood, and these cells quickly migrate to sites of infection and engulf and kill pathogens by releasing proteases and producing large amounts of reactive oxygen species (ROS) [36]
Oxidase activity; excess degranulation observed in Hv1/VSOP-deficient neutrophils was suppressed when the activity of the oxidase was inhibited by the NADPH oxidase inhibitor, diphenyleneiodonium (DPI) [29]

Summary

Introduction

Voltage-gated proton channels are highly proton-selective channels. Proton currents were first recorded from snail neurons in 1982 [1], but their molecular basis remained unidentified for more than two decades. Inhibiting the voltage-gated proton channel increased the depolarization of PMA-stimulated neutrophils [34]. These results indicate that voltagegated proton channels compensate for charge imbalances caused by the activation of Neutrophils normally circulate in blood, and these cells quickly migrate to sites of infection and engulf and kill pathogens by releasing proteases and producing large amounts of reactive oxygen species (ROS) [36]. Voltage-gated proton channels inhibit depolarization induced by NADPH oxidase activation [34].

Results

Conclusion