Schematic representation of gating models of eukaryotic sodium channels. (A) Transmembrane topology of a eukaryotic Nav channel. The S4 voltage-sensing segment is shaded in gray, and the P-loop constitutes the selectivity filter region. The inactivation motif (cerulean-colored box) is the loop connecting domains III and IV. (B) Representative membrane currents through a voltage-activated sodium channel in response to a depolarizing pulse from a holding potential of −90 mV. The start of the depolarization pulse is represented as a break, and the gating current component has been subtracted. (C) Schematic rendering of the original HH model of sodium channel gating. Rapid activation of three “m” particles is sufficient for the channel to open, and slower activation of the “h” particle causes the channel to inactivate. (D) In the coupled inactivation model, activation of all four voltage sensors contributes to the channel opening. Inactivation results from binding of the inactivation lid to its receptor in the pore, which becomes accessible in the open state. (E) According to the asynchronous gating model, the activation of the first three VSDs of the sodium channel is sufficient to open the channel. Slow activation of the domain IV voltage sensor results in a secondary open state and makes the receptor for inactivation lid accessible.
