Structural mechanism of glutamate receptor activation and desensitization.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Meyerson, JR; Kumar, J; Chittori, S; Rao, P; Pierson, J; Bartesaghi, A; Mayer, ML; Subramaniam, S

Published Date

  • October 2014

Published In

Volume / Issue

  • 514 / 7522

Start / End Page

  • 328 - 334

PubMed ID

  • 25119039

Pubmed Central ID

  • 25119039

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature13603

Language

  • eng