Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain

David M. Schauder, Oleg Kuybeda, Jinjin Zhang, Katherine Klymko, Alberto Bartesaghi, Mario J. Borgnia, Mark L. Mayer, Sriram Subramaniam

Research output: Contribution to journalArticle

Abstract

Glutamate receptor ion channels are membrane proteins that mediate excitatory synaptic transmission in the central nervous system of vertebrates. Insight into molecular mechanisms underlying glutamate receptor gating is limited by lack of structural information for receptors trapped in different conformational states. Here,we report the use of single-particle cryoelectron tomography to determine the structures,at ∼21 Åresolution, of full-length GluK2 kainate receptors trappedinantagonist-boundrestingand agonist-bounddesensitized states. The resting state, stabilized by the competitive antagonist LY466195, closely resembles the crystal structure of the AMPA receptor GluA2, with well-resolved proximal and distal subunits exhibiting cross-over between the twofold symmetric amino terminal domain and a twofold symmetric ligand binding domain (LBD) dimer of dimers assembly. In the desensitized state, the LBD undergoes a major rearrangement, resulting in a separation of the four subunits by ∼25 Å. However, the amino terminal domain, transmembrane, and cytoplasmic regions of the receptor have similar conformations in the resting and desensitized states. The LBD rearrangement was not anticipated in prior models based on crystal structures for soluble LBD dimer assemblies, and we speculate that subunit separation allows a better match to the fourfold symmetric ion channel domain. From fits of the amino terminal domain and LBD domains into the density map of the desensitized state we have derived a structural model for differences in quaternary conformation between the resting and desensitized states.

Original languageEnglish (US)
Pages (from-to)5921-5926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number15
DOIs
StatePublished - Apr 9 2013
Externally publishedYes

Keywords

  • Cryoelectron microscopy
  • Ion channel gating

ASJC Scopus subject areas

  • General

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