Voltage-dependent regulation of modal gating in the rat SkM1 sodium channel expressed in Xenopus oocytes

Abstract

The TTX-sensitive rat skeletal muscle sodium channel (rSkM1) exhibits two modes of inactivation (fast vs slow) when the α subunit is expressed alone in Xenopus oocytes. In this study, two components are found in the voltage dependence of normalized current inactivation, one having a V( 1/2 ) in the expected voltage range (~ -50 mV, I(N)) and the other with a more hyperpolarized V( 1/2 ) (~ -130 mV, I(H)) at a holding potential of -90 mV. The I(N) component is associated with the gating mode having rapid inactivation and recovery from inactivation of the macroscopic current (N-mode), while I(H) corresponds to the slow inactivation and recovery mode (H-mode). These two components are interconvertible and their relative contribution to the total current varies with the holding potential: I(N) is favored by hyperpolarization. The interconversion between the two modes is voltage dependent and is well fit to a first-order two-state model with a voltage dependence of e-fold/8.6 mV and a F( 1/2 ) of -62 mV. When the rat sodium channel β1-subunit is coinjected with rSkM1, I(H) is essentially eliminated and the inactivation kinetics of macroscopic current becomes rapid. These two current components and their associated gating modes may represent two conformations of the α subunit, one of which can be stabilized either by hyperpolarization or by binding of the β1 subunit.