Structure of a human synaptic GABA A receptor

Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27.

Abstract

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABAA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodiazepines / antagonists & inhibitors
  • Benzodiazepines / chemistry
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology
  • Bicuculline / pharmacology
  • Binding, Competitive / drug effects
  • Brain Chemistry
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cryoelectron Microscopy*
  • Flumazenil / chemistry
  • Flumazenil / metabolism
  • Flumazenil / pharmacology
  • GABA Modulators / chemistry
  • GABA Modulators / metabolism
  • GABA Modulators / pharmacology
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Immunoglobulin Fab Fragments / immunology
  • Ligands
  • Models, Molecular
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / immunology
  • Receptors, GABA-A / metabolism
  • Receptors, GABA-A / ultrastructure*
  • gamma-Aminobutyric Acid / chemistry
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • GABA Modulators
  • Immunoglobulin Fab Fragments
  • Ligands
  • Receptors, GABA-A
  • Benzodiazepines
  • Flumazenil
  • gamma-Aminobutyric Acid
  • Bicuculline