S4helix

S4helix is a term used in the study of voltage-gated ion channels to denote the fourth transmembrane segment that forms part of the voltage-sensing domain. In many channel families, the S4 helix is distinguished by a repeating motif of positively charged residues (arginine or lysine) at roughly every third position, which contributes to the electric charge moved during voltage sensing.

Location and architecture: The S4 helix typically lies within the S1–S4 domain of the channel, spans the membrane as an alpha helix, and its movement triggers conformational changes in the pore-lining S5–S6 segments orchestrated by interactions with neighboring helices.

Mechanism: Upon membrane depolarization, the electric field exerts force on the positively charged gating charges, causing the S4 helix to undergo axial translation and rotation. This movement is coupled to opening of the pore and ion conduction.

Variations and evidence: S4 properties vary among channel families; structural studies provide models of S4 motion, and mutations in S4 can alter activation voltage and kinetics, with implications for channelopathies—diseases linked to faulty voltage-gated channel function.

Research and applications: The S4 helix remains a focus in biophysics, pharmacology, and channel engineering, informing gating models and guiding drug design or optogenetic approaches.