Two mutations in the IV/S4-S5 segment of the human skeletal muscle Na+ channel disrupt fast and enhance slow inactivation

Fast and slow inactivation (FI, SI) of the voltage-gated Na+ channel are tw o kinetically distinct and structurally dissociated processes. The voltage sensor IV/S4 and the intracellular IV/S4-S5 loop have been shown to play an important role in FI mediating the coupling between activation and inactiv ation. Two mutations in IV/S4-S5 of the human muscle Na+ channel, L1482C/A, disrupt FI by inducing a persistent Na+ current, shifting steady-state ina ctivation in the depolarizing direction and accelerating its recovery. Thes e effects were more pronounced for L1482A. In contrast, SI of L1482C/A chan nels was enhanced showing a more complete SI and a 3-fold slowing of its re covery. Effects on SI were more pronounced for L1482C. The results indicate an important role of the IV/S4-S5 loop not only in Fl but also in SI of th e Na+ channel. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.