Knowledge about the mechanism of impulse blockade by local anesthetics has evolved over the past four decades, from the realization that Na+ channels were inhibited to affect the impulse blockade to an identification of the amino acid residues within the Na+ channel that bind the local anesthetic molecule. Within this period appreciation has grown of the state-dependent nature of channel inhibition, with rapid binding and unbinding at relatively high affinity to the open state, and weaker binding to the closed resting state. Slow binding of high affinity for the inactivated state accounts for the salutary therapeutic as well as the toxic actions of diverse class I anti-arrhythmic agents, but may have little importance for impulse blockade, which requires concentrations high enough to block the resting state. At the molecular level, residues on the S6 transmembrane segments in three of the homologous domains of the channel appear to contribute to the binding of local anesthetics, with some contribution also from parts of the selectivity filter. Binding to the inactivated state, and perhaps the open state, involves some residues that are not identical to those that bind these drugs in the resting state, suggesting spatial flexibility in the "binding site". Questions remaining include the mechanism that links local anesthetic binding with the inhibition of gating charge movements, and the molecular nature of the theoretical "hydrophobic pathway" that may be critical for determining the recovery rates from blockade of closed channels, and thus account for both therapeutic and cardiotoxic actions.

中文翻译：

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局部麻醉剂对钠通道的状态依赖性抑制：40 年的演变。

关于局麻药脉冲阻断机制的知识在过去的 40 年里不断发展，从认识到 Na+ 通道被抑制影响脉冲阻断，到识别 Na+ 通道内与局部麻醉剂分子结合的氨基酸残基。在此期间，人们对通道抑制的状态依赖性性质越来越了解，与开放状态以相对较高的亲和力快速结合和解除结合，而与关闭静息状态的结合较弱。对灭活状态的高亲和力的缓慢结合解释了有益的治疗以及多种 I 类抗心律失常药物的毒性作用，但对冲动阻断可能没有什么重要性，这需要足够高的浓度来阻断静息状态。在分子水平上，通道的三个同源域中 S6 跨膜片段上的残基似乎有助于局部麻醉剂的结合，部分选择性过滤器也有一些贡献。结合到灭活状态，也许是开放状态，涉及一些与在静息状态下结合这些药物的残基不同的残基，表明“结合位点”的空间灵活性。剩下的问题包括将局麻药结合与门控电荷运动的抑制联系起来的机制，以及理论“疏水通路”的分子性质，这可能对确定封闭通道阻塞的恢复率至关重要，因此可以解释两种治疗方法。和心脏毒性作用。