Voltage-Sensor Domain Proteins: Phosphoinositide Signal, Proton Permeation and Molecular Tools

Abstract

Voltage-sensor domain (VSD) is the key transmembrane module for sensing membrane voltage in voltage-gated ion channels and voltage-sensing phosphatase. Hv1 (also called VSOP) mainly expressed in phagocytes and human sperm consists only of VSD and the coiled-coil region, operating as the voltage-gated proton channel. In Hv1, VSD plays dual roles of pH-dependent voltage sensing and proton-selective permeation. These properties are innate to protomer. However, dimerization of Hv1 enables cooperative voltage-dependent gating. The voltage-sensing phosphatase, VSP, is the voltage-activated phosphoinositide phosphatase in which single VSD is tightly coupled with the phosphatase with significant homology to the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Phosphoinositides such as PIP3 and PI(4,5)P2 are dephosphorylated by VSP upon membrane depolarization. Physiological functions of VSP are largely unknown but fibroblasts heterologously expressing VSP exhibit neurite-like fine processes, raising a possibility that VSP may play role in regulating cell shape by phosphoinositide turnover. VSP itself is a useful tool to rapidly manipulate phosphoinositide level by simple membrane depolarization to study roles of phosphoinositides that play roles in diverse biological events. VSD of voltage sensor domain proteins could also be utilized as a molecular material to devise voltage probe for visualizing electrical activities in cells and tissues. I will talk about recent findings of molecular mechanisms of VSP and Hv1 and examples of molecular tools based on VSP.