Shared structural mechanisms of general anaesthetics and benzodiazepines

• Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1–5. 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 GABAA 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 GABAA 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 GABAA 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. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

4 aminobutyric acid

4 aminobutyric acid A receptor

benzodiazepine derivative

bicuculline

diazepam

etomidate

flumazenil

intravenous anesthetic agent

phenobarbital

picrotoxin

propofol

4 aminobutyric acid A receptor blocking agent

anesthetic agent

barbituric acid derivative

ligand

anesthetic

biochemistry

inhibition

membrane

physiological response

protein

signaling

affinity labeling

allosterism

Article

complex formation

conformational transition

controlled study

cryoelectron microscopy

drug binding site

human

human cell

molecular dynamics

mutagenesis

priority journal

binding competition

binding site

chemistry

conformation

drug effect

electrophysiology

metabolism

molecular model

ultrastructure

Allosteric Regulation

Anesthetics

General

Barbiturates

Benzodiazepines

Binding Sites

Binding

Competitive

GABA-A Receptor Antagonists

gamma-Aminobutyric Acid

Humans

Ligands

Models

Molecular

Molecular Conformation

Molecular Dynamics Simulation

Receptors

GABA-A

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)