a gating model for wildtype and r1448H nav1.4 channels in paramyotonia

摘要: We studied the consequences of Nav1.4 mutation R1448H that is situated in fourth voltage sensor channel and causes paramyotonia, a cold-induced myotonia followed by weakness. Previous work showed uncouples inactivation from activation. measured whole-cell Na(+) currents at 10, 15, 20, 25°C using HEK293 cells stably transfected with wildtype (WT) channels. A Markov model was developed parameters which reproduced data on WT channels whole temperature range. It required an additional transient inactivated state closed-state transition not previously described. The used to predict single-channel properties, free energy barriers dependence rates. allowed us draw following conclusions: i) open-state results two-step process; ii) re-openings cause paramyotonia originate enhanced deactivation/reactivation destabilized inactivation; iii) strikingly enhanced. assume latter explains episodic weakness myotonia.