EFFECTS OF GENERAL ANESTHETICS ON NICOTINIC MEMBRANES

大多数全身麻醉药的效力可以通过共享的 物理特性、脂类溶解性。这最初导致了假设 麻醉剂在脂膜上起作用，最近又有了 麻醉药对高脂血症患者血脂影响的动机研究 合成膜和生物膜。这些研究启发了更多的人 全身麻醉作用的详细理论，每一种都具体说明 膜脂的某些基本扰动(例如，破坏相 分离或脂质紊乱)。但这些理论有一些共同之处 明显的弱点。首先，每种脂质的作用机制 扰动导致的不兴奋是模糊的。其次，它们并不比 预测效价比单独预测整体脂类的溶解度要成功。 第三，尽管这些基于脂质的理论产生了可检验的预测， 在这一领域做的工作很少。 一种更机械化的方法是观察一般情况下 麻醉剂在高度纯化的靶结构上，以及相关的结构 对功能的更改。烟碱型乙酰胆碱受体丰富的膜 海洋射线、鱼雷的电风琴可以隔离在 适合分子水平研究的丰度和纯度。这个 乙酰胆碱受体的结构比任何 其他离子通道，其功能性质也在很大程度上是已知的 细节。乙酰胆碱受体最近被用来阐明 现代麻醉实践中必不可少的其他药物的膜作用， 局麻药、巴比妥酸盐和松弛药。一名员工的能力 化学和物理上不同的全麻药组(例如 挥发物、醇、烷烃、惰性气体、氟化气体、甾醇、长 链醇和烷烃)来使受体减敏，将通过 放射性配基(~3H-ACh)结合技术。同时，麻醉效果 关于整体脂膜和脂蛋白界面的研究 通过自旋标记法。这些结构不同的生物的能力 全麻药和改变~3H-ACh结合的压力平行于其 有能力扰乱脂肪吗？

The potency of most general anesthetics can be predicted by a shared physical feature, lipid solubility. This originally led to the hypothesis that anesthetics worked on the lipid membrane, and more recently has motivated investigations of the effects of anesthetics on the lipids of synthetic and biological membranes. These studies have inspired more detailed theories of general anesthetic action, each of which specifies some essential perturbation of membrane lipid (e.g. disrupting phase separations or lipid disordering). But such theories share some conspicuous weaknesses. First, the mechanism by which each lipid perturbation leads to inexcitability is vague. Second, they are not more successful at predicting potency than is bulk lipid solubility alone. Third, although these lipid-based theories generate testable predictions, very little work has been done in this area. A more mechanistic approach is to observe the effects of general anesthetics on a highly purified target structure, and relate structural changes to function. Nicotinic acetylcholine receptor-rich membranes from the electric organ of the marine ray, Torpedo can be isolated in the abundance and purity appropriate for molecular level studies. The structure of the acetylcholine receptor is known better than that of any other ion channel, and the functional properties are also known in great detail. The acetylcholine receptor has recently been used to elucidate the membrane actions of other drugs essential to modern anesthetic practice, the local anesthetics, barbiturates, and relaxants. The ability of a chemically and physically diverse group of general anesthetics (e.g. volatiles, alcohols, alkanes, inert gases, fluorinated gases, sterols, long chain alcohols and alkanes) to desensitize the receptor will be studied by radioligand (3H-ACh) binding techniques. In parallel, anesthetic effects on the bulk lipid membrane and the lipid-protein interface will be studied by spin-labeling methods. Does the ability of these structurally diverse general anesthetics and pressure to alter 3H-ACh binding parallel their ability to perturb lipid?