Open AccessShared structural mechanisms of general anaesthetics and benzodiazepines
Author(s) -
Jeong Joo Kim,
Anant Gharpure,
Jian Teng,
Yinghong Zhuang,
Rebecca J. Howard,
Shaotong Zhu,
Colleen Noviello,
Richard M. Walsh,
Erik Lindahl,
Ryan Hibbs
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2654-5
Subject(s) - gabaa receptor , allosteric regulation , flumazenil , benzodiazepine , chemistry , etomidate , pharmacology , receptor , inhibitory postsynaptic potential , flunitrazepam , diazepam , gabaa rho receptor , neuroscience , propofol , biochemistry , medicine , biology
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1-5 . 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 A 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 A 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 A 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.