Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden.
Nature. 2020 Sep;585(7824):303-308. doi: 10.1038/s41586-020-2654-5. Epub 2020 Sep 2.
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA) receptors to dampen neuronal activity in the brain. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
大多数全身麻醉剂和经典苯二氮䓬类药物通过正向调节γ-氨基丁酸 A 型（GABA）受体来抑制大脑中的神经元活动。然而，在生理受体部位，关于全身麻醉剂作用机制的直接结构信息仍然缺乏。在这里，我们展示了与静脉麻醉剂、苯二氮䓬类药物和抑制性调节剂结合的 GABA 受体的冷冻电镜结构。这些结构是在类脂环境中解决的，并通过电生理学和分子动力学模拟进行了补充。与麻醉剂苯巴比妥、依托咪酯和异丙酚结合的 GABA 受体的结构揭示了独特和共同的跨膜结合位点，部分与苯二氮䓬类药物地西泮共享。GABA 受体与苯二氮䓬类药物结合的结构确定了地西泮的另一个膜结合位点，并提出了氟马西尼通过变构机制逆转麻醉的机制。这项研究为理解药理学上不同且临床上重要的药物如何通过重叠和不同的机制增强大脑中的抑制性信号提供了基础。
