State-Dependent Inhibition of Sodium Channels by Local Anesthetics: A 40-Year Evolution.
State-Dependent Inhibition of Sodium Channels by Local Anesthetics: A 40-Year Evolution.
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DOI：
10.1134/s1990747812010151
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Strichartz GR
中科院分区：
文献类型：
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作者：
Wang GK;Strichartz GR
在过去的四十年里，关于局部麻醉剂脉冲阻断机制的知识不断发展，从认识到Na+通道被抑制以影响脉冲阻断，到鉴定Na+通道内结合局部麻醉剂分子的氨基酸残基。在此期间，通道抑制的状态依赖性逐渐增强，与开放状态的结合和解结合相对较高，与封闭静息状态的结合较弱。对失活状态的高亲和力的缓慢结合解释了各种I类抗心律失常药物的有益治疗和毒性作用，但对冲动阻断可能不太重要，这需要足够高的浓度来阻断静息状态。在分子水平上，通道中三个同源结构域的S6跨膜片段上的残基似乎有助于局部麻醉剂的结合，选择性过滤器的部分也有一定的贡献。结合到失活状态，也许是开放状态，涉及到一些残基，这些残基与在静息状态下结合这些药物的残基不相同，这表明“结合位点”的空间灵活性。仍然存在的问题包括将局部麻醉剂结合与门控电荷运动的抑制联系起来的机制，以及理论上的“疏水途径”的分子性质，这可能对确定封闭通道阻断后的恢复速率至关重要，因此可以解释治疗和心脏毒性作用。
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.