Bertaccini Edward J
Department of Anesthesia, Stanford University School of Medicine, Co-Director of Operating Room and Intensive Care Services, Palo Alto VA Health Care System, 112A, PAVAHCS, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
Pharmaceuticals (Basel). 2010 Jul 8;3(7):2178-2196. doi: 10.3390/ph3072178.
For over 160 years, general anesthetics have been given for the relief of pain and suffering. While many theories of anesthetic action have been purported, it has become increasingly apparent that a significant molecular focus of anesthetic action lies within the family of ligand-gated ion channels (LGIC's). These protein channels have a transmembrane region that is composed of a pentamer of four helix bundles, symmetrically arranged around a central pore for ion passage. While initial and some current models suggest a possible cavity for binding within this four helix bundle, newer calculations postulate that the actual cavity for anesthetic binding may exist four helix bundles. In either scenario, these cavities have a transmembrane mode of access and may be partially bordered by lipid moieties. Their physicochemical nature is amphiphilic. Anesthetic binding may alter the overall motion of a ligand-gated ion channel by a "foot-in-door" motif, resulting in the higher likelihood of and greater time spent in a specific channel state. The overall gating motion of these channels is consistent with that shown in normal mode analyses carried out both as well as in explicitly hydrated lipid bilayer models. Molecular docking and large scale molecular dynamics calculations may now begin to show a more exact mode by which anesthetic molecules actually localize themselves and bind to specific protein sites within LGIC's, making the design of future improvements to anesthetic ligands a more realizable possibility.
160多年来，一直使用全身麻醉剂来减轻疼痛和痛苦。尽管人们提出了许多麻醉作用理论，但越来越明显的是，麻醉作用的一个重要分子焦点在于配体门控离子通道（LGIC）家族。这些蛋白质通道有一个跨膜区域，由四个螺旋束的五聚体组成，围绕着一个用于离子通过的中心孔对称排列。虽然最初的模型和一些当前模型表明在这个四螺旋束内可能存在一个结合腔，但新的计算推测麻醉剂结合的实际腔可能存在于四个螺旋束之外。在任何一种情况下，这些腔都有跨膜的进入方式，并且可能部分地由脂质部分界定。它们的物理化学性质是两亲性的。麻醉剂结合可能通过“脚踏入门”基序改变配体门控离子通道的整体运动，导致处于特定通道状态的可能性更高且持续时间更长。这些通道的整体门控运动与在真空中以及在明确水合的脂质双层模型中进行的正常模式分析中显示的运动一致。分子对接和大规模分子动力学计算现在可能开始展示麻醉剂分子实际定位并结合到LGIC内特定蛋白质位点的更精确模式，使未来改进麻醉剂配体的设计成为更切实可行的可能性。
