Mechanism of Action of Volatile Anesthetics

描述（由申请人提供）：尽管有大量的研究，没有 研究已经产生了一个明确的分子图像的作用位点， 挥发性麻醉剂然而，挥发性麻醉剂似乎破坏了一个非常 神经元功能的基本过程，一个似乎是高度 在许多不同的门中都是保守的。这种基本功能最适合于 在简单的动物模型中进行遗传分析，随后扩展到更多 复杂的有机体因此，我们使用C。作为一种动物， 定义麻醉剂作用部位的分子成分的模型。 我们已经分离出C.控制着 对一系列气态麻醉剂的敏感性。我们的研究结果表明， 基因unc-1编码的蛋白质是至少一个这样的位点的组分， 挥发性麻醉剂的作用。我们克隆并鉴定了UNC-1 C.优雅unc-1编码哺乳动物的一个密切同源物， 蛋白质，即气孔蛋白，它在控制离子穿过细胞的过程中起重要作用 膜。其它资料表明，UNC-1可能在麻醉药中发挥作用 通过与称为脂筏的膜微区相互作用来响应。我们有 表明C. elegans，而ESTA-1与 这些木筏一系列影响细胞生理学的蛋白质已经被证明 与脂筏有关。 Unc-1在C.主要分布在 神经系统该蛋白与钠离子通道和一种新的 G蛋白偶联受体控制麻醉药敏感性。的同源物 这些蛋白质中的每一种都是受影响的与气孔蛋白相关的蛋白质复合体的一部分， 吸入挥发性麻醉剂该项目的具体目标是：1。到 更充分地表征了与口朊相关的复合控制麻醉剂， 敏感性C。优雅2.对C.优雅的 然后将研究其它蛋白质与这些微区的结合。3. 观察麻醉药对小鼠胃蛋白缺乏的影响。这种方法 是成功使用模型系统（如C）的逻辑扩展。 elegans来证明它对哺乳动物的适用性。

DESCRIPTION (provided by applicant): Despite a great deal of research, no studies have yielded a definitive molecular picture of a site of action of volatile anesthetics. However, volatile anesthetics appear to disrupt a very fundamental process of neuronal function, one that appears to be highly conserved across many disparate phyla. Such a basic function is best suited to genetic analysis in a simple animal model with later extension into more complicated organisms. For this reason, we are using C. elegans as an animal model in which to define molecular components of anesthetic sites of action. We have isolated mutations in several genes in C. elegans that control sensitivity to an array of gaseous anesthetics. Our results indicate that the gene unc-1 codes for a protein that is a component of at least one such site of action for volatile anesthetics. We have cloned and characterized the unc-1 gene from C. elegans. unc-1 codes for a close homologue of the mammalian protein, stomatin, which is important in controlling ion flux across cell membranes. Other data indicates that unc-1 may exert its effect on anesthetic response by interacting with membrane microdomains called lipid rafts. We have shown that lipid rafts exist in C. elegans and that UNC-1 is associated with these rafts. A wide array of proteins affecting cell physiology have been shown to be associated with lipid rafts. Unc-1 is expressed at all postembryonic times in C. elegans, primarily in the nervous system. The UNC-1 protein interacts with a sodium channel and a novel G-protein coupled receptor to control anesthetic sensitivity. Homologues of each of these proteins are part of a stomatin-related protein complex affected by volatile anesthetics. The specific aims of this project are: 1. To characterize more fully the stomatin-related complex controlling anesthetic sensitivity in C. elegans. 2. To characterize lipid rafts from C. elegans. The association of other proteins with these micro domains will then be studied. 3. To measure the effects of anesthetics on stomatin deficient mice. This approach is the logical extension of the successful use of a model system such as C. elegans to demonstrate its applicability to mammals.