Wang G-K, Strichartz G R
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston MA 02115, USA.
Biochem (Mosc) Suppl Ser A Membr Cell Biol. 2012 Apr;6(2):120-127. doi: 10.1134/S1990747812010151.
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.
在过去的四十年里，关于局部麻醉药冲动阻断机制的认识不断发展，从意识到钠通道被抑制以影响冲动阻断，到确定钠通道内与局部麻醉药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本质的认识不断加深，其对开放状态具有相对较高亲和力的快速结合和解离，而对静息关闭状态的结合较弱。对失活状态具有高亲和力的缓慢结合解释了多种I类抗心律失常药物的有益治疗作用和毒性作用，但对于需要足够高浓度以阻断静息状态的冲动阻断可能不太重要。在分子水平上，通道三个同源结构域中S6跨膜片段上的残基似乎有助于局部麻醉药的结合，选择性过滤器的部分区域也有一定贡献。与失活状态以及可能的开放状态的结合涉及一些与静息状态下结合这些药物的残基不同的残基，这表明“结合位点”具有空间灵活性。仍然存在的问题包括将局部麻醉药结合与门控电荷运动抑制联系起来的机制，以及理论上“疏水途径”的分子性质，这可能对确定关闭通道阻断后的恢复速率至关重要，从而解释治疗作用和心脏毒性作用。
