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Review
. 2021 Mar 5;22(5):2620.
doi: 10.3390/ijms22052620.

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

Yoshifumi Okochi  1 , Yasushi Okamura  1   2
Affiliations
Review

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

Yoshifumi Okochi et al. Int J Mol Sci. .

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.

Keywords: Ca2+; NADPH oxidase; ROS; degranulation; membrane potential; migration; neutrophils; pH; phagocytes; voltage-gated proton channel.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hv1/VSOP maintains NADPH oxidase activity in neutrophils. Activation of NADPH oxidase depolarizes membrane potential. This is dampened by the activation of Hv1/VSOP, which compensates for charge imbalance [22]. Protons released into the cytoplasm upon NADPH oxidase activation are extruded by Hv1/VSOP outside the cell or into phagosomes to produce H2O2 and to maintain neutral phagosomal pH [22]. Thus, Hv1/VSOP has dual functions; inhibition of membrane depolarization and acidification of cytoplasm by extruding protons. Both lead to sustained ROS production by NADPH oxidase [12,22,26,28]. Arrow and T arrow indicate promotion and inhibition, respectively, for Vm and pH.
Figure 2
Figure 2
Hv1/VSOP inhibits degranulation in neutrophils. Hv1/VSOP inhibits degranulation of primary granules by regulating charge imbalance accompanied by NADPH oxidase activation [29]. Arrow and T arrow indicate promotion and inhibition, respectively, for Vm, pH and degranulation of primary granules. MPO is myeloperoxidase.
Figure 3
Figure 3
Hv1/VSOP controls the migration of neutrophils by positively and negatively regulating ROS production. In the presence of high dose of fMIVIL, Hv1/VSOP promotes Ca2+ influx at the plasma membrane by suppressing depolarization induced by NAPDH oxidase [22]. This is necessary for the proper movement of neutrophils in response to fMIVIL [22]. In the presence of low doses of fMLF, Hv1/VSOP inhibits ROS production [25], leading to the suppression of extracellular signal-regulated kinase (ERK) activity and migration of neutrophils in response to fMLF [25]. Arrow and T arrow indicate promotion and inhibition, respectively, for Vm, pH, Ca2+, ROS and so on.
Figure 4
Figure 4
Hv1/VSOP is two-way player regulating ROS production in neutrophils. Under conditions of phagocytosis, which requires a large production of ROS, Hv1/VSOP promotes ROS production to compensate charge imbalance induced by NADPH oxidase activation [12,22,26,28]. However, under conditions when a small amount of ROS is produced, Hv1/VSOP inhibits ROS production [25], which might be regulated through actin remodeling [20,22]. Arrow and T arrow indicate promotion and inhibition, respectively, for Vm, pH, ROS and actin remodeling. Red and blue arrow indicate increase and decrease of ROS production, respectively.
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