E1784K alters voltage-dependent and voltage-independent rates of the sodium channel fast inactivation process. (A) Schematic model of two-step sodium channel fast inactivation. The first step is the voltage-dependent activation (white to black) of the DIV voltage sensor. The activation and deactivation rates of this first step determine the voltage dependence, recovery rate, and onset rate of fast inactivation. The second step is the voltage-independent binding of the IFM motif to occlude the channel pore. The ratio of forward and reverse binding rates for IFM determines the fraction of noninactivating current in E1784K. In addition, the forward binding rate determines the maximal fast-inactivation rate at highly depolarized potentials. (B) Simulated macroscopic currents for E1784E (black), E1784K (red), E1784V (blue), E1784W (green), K1493E/E1784K (purple), and K1641D (orange) models in response to depolarizing steps between −100 and +40 mV from a holding potential of −130 mV. (C) Simulated (lines; Sim.) and experimental (symbols; Exp.) voltage dependence of fast inactivation for Nav1.5 variants. (D) Simulated noninactivating currents for Nav1.5 variants at −20 mV normalized to peak inward current. (E) Simulated (lines) and experimental (symbols) recovery time courses from fast inactivation for Nav1.5 variants. (F) Simulated (lines) and experimental (symbols) onset time courses of fast inactivation for Nav1.5 variants.