Figure 9. Promoting entry into the slow-inactivated state reduces voltage-gated sodium current (I_NaR) amplitudes.

(A) Mean ± SEM peak I_NaR amplitudes, measured on membrane hyperpolarizations following brief depolarizing voltage steps to +10 mV, in wild type (black) and Scn4b^-/- (red) mouse cerebellar Purkinje neurons are plotted as a function of membrane voltage are shown (data were reproduced with permission from Ransdell et al., 2017). Peak I_NaR amplitudes in individual wild type and Scn4b^-/- cells were also normalized to peak I_NaT measured (at 0 mV) in the same cell, and the mean I_NaR as a percentage of peak I_NaT in wild type (black) and Scn4b^-/- (red) cells are plotted (as points) in (B); the solid line is the normalized relative I_NaR/I_NaT generated by the Scn4b^-/- model. (C) Consistent with the experimental data, the kinetics of I_NaR are not affected measurably by the loss of Scn4b (Navβ4) in the model, whereas I_NaR amplitudes are reduced to ~50% of wild type I_NaR levels (C). A time-locked plot of the gating state transitions (D) indicates that I_NaR amplitudes are reduced in the Scn4b^-/- model (dashed lines) due to a decrease in IF2 occupancy and an increase in IS occupancy. In this gating state occupancy plot, black represents the closed state, blue represents the open state, green represents the IC1+ IC2 states, aqua represents the IF2 state, orange represents the IF1 state, and purple represents the IS state.