Structural mechanism of glutamate receptor activation and desensitization

Nature. 2014 Oct 16;514(7522):328-34. doi: 10.1038/nature13603. Epub 2014 Aug 3.

Abstract

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the vertebrate brain. To gain a better understanding of how structural changes gate ion flux across the membrane, we trapped rat AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional states and analysed the resulting structures using cryo-electron microscopy. We show that transition to the active state involves a 'corkscrew' motion of the receptor assembly, driven by closure of the ligand-binding domain. Desensitization is accompanied by disruption of the amino-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry transition in the ligand-binding domains in both subtypes. The 7.6 Å structure of a desensitized kainate receptor shows how these changes accommodate channel closing. These findings integrate previous physiological, biochemical and structural analyses of glutamate receptors and provide a molecular explanation for key steps in receptor gating.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Binding Sites
  • Cryoelectron Microscopy*
  • Glutamic Acid / chemistry
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology
  • Ion Channel Gating / drug effects
  • Ligands
  • Models, Molecular
  • Protein Structure, Tertiary / drug effects
  • Rats
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / metabolism*
  • Receptors, AMPA / ultrastructure*
  • Receptors, Kainic Acid / chemistry
  • Receptors, Kainic Acid / metabolism*
  • Receptors, Kainic Acid / ultrastructure*

Substances

  • Gluk2 kainate receptor
  • Ligands
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Glutamic Acid
  • glutamate receptor ionotropic, AMPA 2

Associated data

  • PDB/4UQ6
  • PDB/4UQJ
  • PDB/4UQK
  • PDB/4UQQ