Olsen R W
Department of Molecular and Medical Pharmacology, School of Medicine, Brain Research Institute, Mental Retardation Research Center, University of California, Los Angeles 90095-1735, USA.
Toxicol Lett. 1998 Nov 23;100-101:193-201. doi: 10.1016/s0378-4274(98)00185-4.
(1) Considerable evidence has accumulated that the molecular target of general anesthetics in the central nervous system is the GABA(A) receptor, the major mediator of inhibitory synaptic transmission. This receptor is actually a family of ligand-gated chloride channel proteins, each a heteropentameric membrane-spanning structure. (2) Regional variation in anesthetic actions on the central nervous system may parallel a corresponding regional variation in pharmacological subtypes of GABA(A) receptors. These result from differential regional expression of approximately 18 subunit genes. (3) Receptors of varying subunit composition show differential sensitivity to GABA, modulatory drugs, and biological regulatory mechanisms. Regional variation in allosteric modulation of GABA(A) receptor binding and function can be reconstituted in certain recombinant receptor subunit combinations expressed in heterologous cells. (5) Differential sensitivity to anesthetics for various GABA(A) receptor subunits also allows the use of the chimeric and site-directed mutagenesis approach in attempting to define domains of the protein which participate in the binding and actions of anesthetics.
(1) 大量证据表明，全身麻醉药在中枢神经系统中的分子靶点是GABA(A)受体，它是抑制性突触传递的主要介质。该受体实际上是一类配体门控氯离子通道蛋白家族，每个都是异五聚体跨膜结构。(2) 麻醉药对中枢神经系统作用的区域差异可能与GABA(A)受体药理学亚型的相应区域差异平行。这些差异源于约18个亚基基因的差异区域表达。(3) 不同亚基组成的受体对GABA、调节药物和生物调节机制表现出不同的敏感性。在异源细胞中表达的某些重组受体亚基组合中，可以重现GABA(A)受体结合和功能变构调节的区域差异。(5) 各种GABA(A)受体亚基对麻醉药的不同敏感性也使得在试图定义参与麻醉药结合和作用的蛋白质结构域时，可以使用嵌合和定点诱变方法。
