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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >The position of the fourth segment of domain 4 determines status of the inactivation gate in Na+ channels.
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The position of the fourth segment of domain 4 determines status of the inactivation gate in Na+ channels.

机译：域4第四段的位置确定了Na +通道中失活门的状态。

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摘要

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 differenteffect 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.
机译：Na +通道中域4（S4 / D4）的第四段是电压传感器，尤其与通道失活有关。尽管有证据表明S4 / D4在膜去极化过程中向外部移动，但该移动是否（以及如何移动）导致失活门的构象变化仍然未知。我们通过残基F1625（即F1625R和F1625K）的点突变在S4 / D4中最外面带电的残基外部添加了一个正电荷。在这些突变通道中的失活曲线以及从失活中恢复的动力学分为两个部分，一个发生在通道激活/失活的情况下，另一个发生在没有通道激活/失活的情况下。好像“额外的”正电荷会诱导S4 / D4的新中间位置，并因此导致新的中间失活状态与通道激活/失活脱钩。 F1625R和F1625K突变体之间在质量上相似但在数量上非常不同的发现进一步表明，由于正电荷的位置略有不同，因此对灭活门的影响也明显不同。另一方面，残基F1625的中性突变不会引起新的失活状态，而是会改变电压轴上不同失活参数的电压依赖性，就好像只有S4 / D4保持其原始最外层和最内层位置的相对趋势是改变了。我们得出的结论是，S4 / D4运动不仅起决定作用，而且还精细地控制了失活门。 S4 / D4的顶部电荷与相应的反电荷之间的静电相互作用可能在确定S4 / D4位置以及因此确定Na +通道的失活状态方面起着至关重要的作用。

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