Shared structural mechanisms of general anesthetics and benzodiazepines

Most general anesthetics and classical benzodiazepines act through positive modulation of γ-aminobutyric acid type A (GABA(A)) receptors to dampen neuronal activity in the brain(1–5). Direct structural information for how these drugs work at their physiological receptor sites is absent for general anesthetics. Here we present high-resolution structures of GABA(A) receptors bound to intravenous anesthetic, benzodiazepine, and inhibitory modulators. These structures were solved in a lipidic environment and complemented by electrophysiology and molecular dynamics simulations. Structures in complex with the anesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, shared in part by the benzodiazepine diazepam. Structures bound by antagonistic benzodiazepine-site ligands identify a novel membrane binding site for diazepam and suggest an allosteric mechanism for anesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinctive mechanisms to potentiate inhibitory signaling in the brain.