A hypothesis about the endogenous analogue of general anesthesia
A hypothesis about the endogenous analogue of general anesthesia
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DOI：
10.1073/pnas.94.25.13375
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发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Lerner, RA
中科院分区：
文献类型：
--
作者：
Lerner, RA
全身麻醉的出现仍然是医学史上最重要的进步之一。虽然第一次流行的全身麻醉演示是150多年前在现在著名的马萨诸塞州总医院的以太圆顶上进行的，但其发生的机制仍然存在争议。令人惊讶的是，在所有关于全身麻醉的问题中，是否存在内源性麻醉过程的重要问题很少被讨论。这种情况有别于通常的事件过程，即发现外源天然产品具有生物活性，因为许多活动都致力于寻找内源对应产品。例如，想想鸦片类药物和内啡肽。作为一个正式的命题，问题是大脑或身体是否会产生具有全身麻醉剂特性和作用模式的化合物。这个问题归结为全身麻醉药在模仿什么，如果有的话，是什么自然过程。这个问题现在浮出水面，因为最近在睡眠剥夺猫的脑脊液(CSF)中发现了一种诱导睡眠的类脂--油酰胺(2，3)。自那以后，油酰胺已被证明影响各种膜蛋白(4)，具有预期扰乱膜脂流动性的结构，并伴随着一种与膜结合的脑酶，可迅速使化合物失活(3，5)。因此，油酰胺的作用方式可能是不寻常的，因为它扰乱了脂类基质，要么是游离的，要么是与蛋白质和蛋白质组合形成络合的。这一概念值得考虑，因为它将代表一种新的调控形式，有别于通常的受体-配体相互作用。关于全身麻醉药的主要化学事实涉及它们的多样性、疏水性和普遍缺乏立体特异性。最古老的关联被称为迈耶-奥弗顿规则，该规则规定全身麻醉剂的强度与其在橄榄油中的溶解度成正比(6)。这一特征必须被认为是麻醉剂一般疏水性的衡量标准，由于关联的显著精确度，它受到了极大的关注。迈耶-奥弗顿关联及其现代对应关系，再加上通常缺乏立体特异性的知识，导致许多人提出全麻药是通过使脑细胞质膜流态化来发挥作用的。事实上，实验研究表明，全麻药是天然和人造膜的有效流动剂。普通麻醉药通过改变膜的整体流动性起作用的简单概念的一个问题是，尽管大量的这些化合物确实使膜流动，但在将这些化合物的浓度限制在实际麻醉条件下大脑中预期存在的浓度的实验中没有观察到流动性变化(7)。这一发现导致一些人假设麻醉剂直接与蛋白质相互作用(8)，另一些人推测它们扰乱了蛋白质-脂质界面上的特殊脂肪基质(9)(图1)。如果后一种假设是真的，并且存在内源性的对应物，那么我们可以期待一种新的转导机制，而不是运行在通常的配体-受体相互作用中，通过扰乱膜蛋白的环境来影响其功能。当这种作用依赖于改变膜的流动性时，这种化合物可以被认为是流动性传递体。这一观点表明，一些膜蛋白对其脂质环境很敏感，膜的改变可以改变这些蛋白质的构象，其方式与蛋白质的二级修饰对…的影响大致相同
The advent of general anesthesia remains one of the most important advances in the history of medicine. Although the first popular demonstration of general anesthesia occurred more than 150 years ago at the now-famous ether dome of the Massachusetts General Hospital, the mechanism by which it occurs is still debated (1). Surprisingly, among all of the questions asked about general anesthesia, the important issue of if there is an endogenous analogue of the process is rarely discussed. This situation is in distinction to the usual course of events when an exogenous natural product is found to have biological activity in that much activity is devoted to a search for the endogenous counterpart. Think, for example, about the opiates and the endorphins. As a formal proposition the question is if the brain or body makes compounds that have the properties and mode of action of general anesthetics. The issue reduces to what, if any, natural process are the general anesthetics mimicking. This question surfaces now because of the recent discovery of a sleep-inducing lipid, oleamide, in the cerebrospinal fluid (CSF) of sleep-deprived cats (2, 3). Oleamide since has been shown to affect diverse membrane proteins (4), has a structure expected to perturb the fluidity of membrane lipids, and is accompanied by a membrane-bound brain enzyme that rapidly inactivates the compound (3, 5). It is therefore possible that the way oleamide operates is unusual in that it perturbs lipid matrices either free or complexed to proteins and protein assemblies. This concept is worth considering because it would represent a new form of regulation distinct from the usual receptor-ligand interaction. The main chemical facts about general anesthetics concern their diverse nature, hydrophobicity, and general lack of stereospecificity. The oldest correlate is called the Meyer–Overton rule, which states that the strength of a general anesthetic is proportional to its solubility in olive oil (6). This feature, which must be considered as a measure of general hydrophobicity of the anesthetic, has received much attention because of the remarkable precision of the correlation. The Meyer–Overton correlation and its modern counterparts together with the knowledge that stereospecificity often is lacking has led many to propose that general anesthetics operate by fluidizing the plasma membrane of brain cells. Indeed, experimental studies have shown that general anesthetics are potent fluidizers of natural and artificial membranes. One problem with the simple notion that general anesthetics operate by altering the bulk fluidity of membranes is that although large quantities of these compounds do fluidize membranes, no fluidity changes are observed in experiments that restrict the concentrations of these compounds to those expected to be present in the brain under actual conditions of anesthesia (7). This finding has led some to postulate that anesthetics directly interact with proteins (8), and others have speculated that they perturb specialized lipid matrices at the protein-lipid interface (9)(Fig. 1). If the latter postulate is true and there is an endogenous counterpart, then we can expect a new kind of transduction mechanism that, rather than operating in the usual ligand-receptor interaction, effects the function of membrane proteins by perturbing their environment. When the effect depends on altering membrane fluidity such compounds can be considered to be fluidity transmitters. This idea implies that some membrane proteins are sensitive to their lipid environment and that membrane alteration can change the conformations of these proteins in much the same way that secondary modifications of proteins …