Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor

  1. Nandish Khanra
  2. Patricia MGE Brown
  3. Amanda M Perozzo
  4. Derek Bowie
  5. Joel Meyerson  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. McGill University, Canada

Abstract

Kainate receptors (KARs) are L-glutamate-gated ion channels that regulate synaptic transmission and modulate neuronal circuits. KARs have strict assembly rules and primarily function as heteromeric receptors in the brain. A longstanding question is how KAR heteromer subunits organize and coordinate together to fulfill their signature physiological roles. Here we report structures of the GluK2/GluK5 heteromer in apo, antagonist-bound, and desensitized states. The receptor assembles with two copies of each subunit, ligand binding domains arranged as two heterodimers, and GluK5 subunits proximal to the channel. Strikingly, during desensitization GluK2 but not GluK5 subunits undergo major structural rearrangements to facilitate channel closure. We show how the large conformational differences between antagonist-bound and desensitized states are mediated by the linkers connecting the pore helices to the ligand-binding domains. This work presents the first KAR heteromer structure, reveals how its subunits are organized, and resolves how the heteromer can accommodate functionally-distinct closed channel structures.

Data availability

Cryo-EM density maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-23017 (GluK2/K5-apo), EMD-23014 (GluK2/K5-CNQX), and EMD-23015 (GluK2/K5-L-Glu). Model coordinates have been deposited in the Protein Data Bank (PDB) under accession numbers 7KS0 (GluK2/K5-CNQX) and 7KS3 (GluK2/K5-L-Glu). Raw cryo-EM data will be publicly available on the EMPIAR repository upon publication under the accession numbers: EMPIAR-10658, EMPIAR-10659, EMPIAR-10660

The following data sets were generated

Article and author information

Author details

  1. Nandish Khanra

    Physiology and Biophysics, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4217-1273
  2. Patricia MGE Brown

    Pharmacology & Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8340-0330
  3. Amanda M Perozzo

    Pharmacology & Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9681-3548
  4. Derek Bowie

    Pharmacology & Therapeutics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9491-8768
  5. Joel Meyerson

    Physiology and Biophysics, Weill Cornell Medical College, New York, United States
    For correspondence
    jrm2008@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6127-0093

Funding

Leon Levy Foundation (N/A)

  • Joel Meyerson

Fonds de Recherche du Québec - Santé (N/A)

  • Patricia MGE Brown

Canadian Institutes of Health Research (136832)

  • Derek Bowie

Canadian Institutes of Health Research (162317)

  • Derek Bowie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Khanra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nandish Khanra
  2. Patricia MGE Brown
  3. Amanda M Perozzo
  4. Derek Bowie
  5. Joel Meyerson
(2021)
Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor
eLife 10:e66097.
https://doi.org/10.7554/eLife.66097

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https://doi.org/10.7554/eLife.66097