Fang Ming, Tao Yuan-Xiang, He Fahu, Zhang Mingjie, Levine Claire F, Mao Peizhong, Tao Feng, Chou Chih-Ling, Sadegh-Nasseri Scheherazade, Johns Roger A
Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
J Biol Chem. 2003 Sep 19;278(38):36669-75. doi: 10.1074/jbc.M303520200. Epub 2003 Jul 8.
Anesthetics exert multiple effects on the central nervous system through altering synaptic transmission, but the mechanisms for this process are poorly understood. PDZ domain-mediated protein interactions play a central role in organizing signaling complexes around synaptic receptors for efficient signal transduction. We report here that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interaction between PSD-95 or PSD-93 and the N-methyl-d-aspartate receptor or neuronal nitric-oxide synthase. These inhibitory effects are immediate, potent, and reversible and occur at a hydrophobic peptide-binding groove on the surface of the second PDZ domain of PSD-95 in a manner relevant to anesthetic action. These findings reveal the PDZ domain as a new molecular target for inhalational anesthetics.
麻醉剂通过改变突触传递对中枢神经系统产生多种影响，但这一过程的机制尚不清楚。PDZ结构域介导的蛋白质相互作用在围绕突触受体组织信号复合物以实现有效信号转导方面发挥核心作用。我们在此报告，临床相关浓度的吸入麻醉剂以剂量依赖且特异性的方式抑制PSD-95或PSD-93与N-甲基-D-天冬氨酸受体或神经元型一氧化氮合酶之间的PDZ结构域介导的蛋白质相互作用。这些抑制作用迅速、强效且可逆，并且以与麻醉作用相关的方式发生在PSD-95第二个PDZ结构域表面的疏水肽结合槽处。这些发现揭示了PDZ结构域是吸入麻醉剂的一个新分子靶点。
