Molecular Basis of Charge Movement in Voltage-Gated Sodium Channels

Voltage-dependent movement of a sodium channel S4 segment was examined by cysteine scanning mutagenesis and testing accessibility of the residues to hydrophilic cysteine-modifying reagents. These experiments indicate that 2 charged S4 residues move completely from an internally accessible to an externally accessible location in response to depolarization by passage through a short “channel” in the protein. The energetic problems of S4 movement have thus been solved in the same way that many ion channels achieve highly selective and rapid ion permeation through an open pore, by restricting the contact region between the permion and its channel.