Voltage Sensor Domains and Closed-State Inactivation in Sodium Channels

Sodium channels enter into a state of fast inactivation after opening, or directly from closed states. We examined the roles of the four voltage sensor domains in hNaV1.4 in closed-state fast inactivation using a mutagenesis approach. Charge reversing mutations of outer arginine residues in domains I, III and IV depolarized the steady-state fast inactivation curve and accelerated entry. Similar effects on closed-state fast inactivation were observed for charge-reversing mutations of inner negative charges in domains I and IV, suggesting that electrostatic interaction of these residues limits S4 translocation in response to sub-threshold depolarization. This work was supported by NIH 2P20GM103408 to ISU.