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The fourth segment of domain 4 (S4/D4) in Na+ channels is a voltage sensor especially implicated in channel inactivation. Although there has been evidence that S4/D4 moves externally during membrane depolarization, whether (and if so, how) the movement leads to conformational changes of the inactivation gate remains unknown. We added a positive charge just external to the outermost charged residue in S4/D4 by point mutations of residue F1625 (i.e., F1625R and F1625K). The inactivation curves as well as the kinetics of recovery from inactivation in these mutant channels are split into two components, one happening with and the other without channel activation/deactivation. This is as if the "extra" positive charge induces new intermediate positions of S4/D4 and consequently new intermediate inactivation states uncoupled from channel activation/deactivation. The qualitatively similar but quantitatively very different findings between the F1625R and F1625K mutants further suggest a significantly different effect on the inactivation gate by a slight difference in the localization of the positive charge. On the other hand, neutral mutations of residue F1625 do not induce new inactivation states but shift the voltage dependence of different inactivation parameters in the voltage axis, as if only the relative tendency of S4/D4 to stay in its original outermost and innermost positions is altered. We conclude that S4/D4 movement not only decisively but also delicately controls the inactivation gate. Electrostatic interaction between the top charges of S4/D4 and the corresponding countercharges may play an essential role in the determination of S4/D4 position and therefore the inactivation status of the Na+ channel.
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