Structural mechanism of glutamate receptor activation and desensitization

Joel R. Meyerson, Janesh Kumar, Sagar Chittori, Prashant Rao, Jason Pierson, Alberto Bartesaghi, Mark L. Mayer, Sriram Subramaniam

Research output: Contribution to journalArticlepeer-review

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 (a-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 ligandbinding 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 A 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.

Original languageEnglish (US)
Pages (from-to)328-334
Number of pages7
JournalNature
Volume514
Issue number7522
DOIs
StatePublished - Aug 3 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

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