Journal Article

Shared structural mechanisms of general anaesthetics and benzodiazepines

Zhu, Shaotong, Gharpure, Anant, Noviello, Colleen M., Hibbs, Ryan E., Zhuang, Yuxuan, Kim, Jeong Joo, Teng, Jinfeng, Howard, Rebecca J., Walsh, Richard M., Lindahl, Erik

2020

Overview

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. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 4 aminobutyric acid / 4 aminobutyric acid A receptor / 4 aminobutyric acid A receptor blocking agent / 631/378/2586 / 631/535/1258/1259 / 631/57/2270/1140 / 82/1 / 82/80 / 82/83 / 9/74 / affinity labeling / Allosteric properties / Allosteric Regulation / Allosteric Regulation - drug effects / allosterism / Analysis / anesthetic / anesthetic agent / Anesthetics / Anesthetics, General - chemistry / Anesthetics, General - metabolism / Anesthetics, General - pharmacology / Barbiturates / Barbiturates - chemistry / Barbiturates - metabolism / Barbiturates - pharmacology / barbituric acid derivative / benzodiazepine derivative / Benzodiazepines / Benzodiazepines - chemistry / Benzodiazepines - metabolism / Benzodiazepines - pharmacology / bicuculline / Bicuculline - chemistry / Bicuculline - metabolism / Bicuculline - pharmacology / Binding / binding competition / binding site / Binding Sites / Binding sites (Biochemistry) / Binding, Competitive - drug effects / biochemistry / chemistry / Competitive / complex formation / conformation / conformational transition / controlled study / Cryoelectron Microscopy / Diazepam / Diazepam - chemistry / Diazepam - metabolism / Diazepam - pharmacology / drug binding site / Drug dosages / drug effect / Drugs / Electron microscopy / Electrophysiology / Etomidate / Etomidate - chemistry / Etomidate - metabolism / Etomidate - pharmacology / Flumazenil / Flumazenil - pharmacology / GABA / GABA-A / GABA-A Receptor Antagonists / GABA-A Receptor Antagonists - chemistry / GABA-A Receptor Antagonists - metabolism / GABA-A Receptor Antagonists - pharmacology / gamma-Aminobutyric Acid / gamma-Aminobutyric Acid - chemistry / gamma-Aminobutyric Acid - metabolism / gamma-Aminobutyric Acid - pharmacology / General anesthetics / human / human cell / Humanities and Social Sciences / Humans / inhibition / Interfaces / Intravenous administration / intravenous anesthetic agent / Labeling / ligand / Ligands / Lipids / membrane / metabolism / Microscopy / Models, Molecular / Modulators / Molecular / Molecular Conformation / Molecular dynamics / Molecular Dynamics Simulation / molecular model / multidisciplinary / Mutagenesis / Neuromodulation / Phenobarbital / Phenobarbital - chemistry / Phenobarbital - metabolism / Phenobarbital - pharmacology / physiological response / picrotoxin / Picrotoxin - chemistry / Picrotoxin - metabolism / Picrotoxin - pharmacology / priority journal / Propofol / Propofol - chemistry / Propofol - metabolism / Propofol - pharmacology / protein / Receptors / Receptors, GABA-A - chemistry / Receptors, GABA-A - metabolism / Receptors, GABA-A - ultrastructure / Science / Science (multidisciplinary) / signaling / Structure / ultrastructure / γ-Aminobutyric acid A receptors