Sodium channel inactivation from closed states: Evidence for an intrinsic voltage dependency

The time course of Na channel inactivation from closed states was determined on inside-out excised patches from neuroblastoma N1E 115, Closed-state inactivation develops as a single exponential with mean time constants of 66.4 ms at -80 mV, 29.6 ms at -70 mV, 20.1 ms at -60 mV, and 15.1 ms at -50 mV. Corresponding mean steady-state values of the fitted exponentials were 0.321, 0.098, 0.035, and 0. Closed-state inactivation, in general, should develop either with a delay or as more than one exponential, depending on which closed state(s) directly inactivate. The absence of additional components cannot be attributed to a rate of exchange between closed states too rapid to detect. The time course is simply accounted for if all closed states directly inactivate and do so with the same rate constant for each dosed state, suggesting that those conformational changes constituting the transitions between closed states have little effect on the structural components involved in inactivation. Closed to inactivated rate constants ranged from a mean of 0.0108 ms(-1) at -80 mV to 0.0690 ms(-1) at -50 mV. This voltage dependency is entirely intrinsic to closed-state inactivation with closed to inactivated rate constants similar for all closed states. Over the potential range studied nearly all the inactivation is from closed states.