Voltage sensors.

Widely distributed in all kingdoms of life, voltage sensors in the membrane serve important functions via their movements driven by changes in voltage across the membrane (membrane potential). A voltage sensor domain contains 4 transmembrane segments (S1-S4). The S1-S3 helices form a hydrophobic constriction site (HCS, also known as the gating charge transfer center) that spans roughly one-third of the membrane thickness. Flanked by aqueous vestibules connected to the extracellular solution above the HCS or cytoplasmic solution below the HCS, the HCS forms a gating pore for the S4 segment bearing multiple basic residues. Membrane potential changes cause S4 to move through the HCS in a 3 helical conformation. This S4 translocation generates a gating current as the positively charged S4 basic residues traverse the membrane electric field, transferring these gating charges from one aqueous vestibule to the other. For voltage-gated ion channels with their voltage sensor domains connected to pore domains, the HCS in the voltage sensor domain allows S4 but not ions to go through, while the channel pore formed by the pore domains mediates ion permeation. Voltage sensor mutations could result in ω currents that are conducted through the gating pore of mutant voltage-gated ion channels. These ω currents may cause pathological consequences in patients with periodic paralysis. Besides voltage-gated ion channels, the sperm-specific Na/H exchanger and voltage-sensing phosphatases contain voltage sensors for membrane potential regulation. Notably, voltage-gated proton channels that are important for pH homeostasis are formed solely by the voltage sensor domain, which mediates proton permeation. SIGNIFICANCE STATEMENT: Voltage sensors mediate voltage regulation of ion channels, transporters, and phosphatases. The voltage sensor domain composed of 4 transmembrane segments (S1-S4) focuses the membrane electric field to the hydrophobic constriction site. To mediate voltage regulation, S4 basic residues within a 3 helix move across the hydrophobic constriction site without concurrent ion flow through this gating pore. As a counterexample, voltage-gated proton channels are formed by the voltage sensor to mediate proton permeation. These ingeniously engineered voltage sensors are conserved throughout evolution.