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.

Reviewing Editor

  1. Merritt Maduke, Stanford University School of Medicine, United States

Publication history

  1. Received: December 29, 2020
  2. Accepted: March 5, 2021
  3. Accepted Manuscript published: March 16, 2021 (version 1)
  4. Version of Record published: March 26, 2021 (version 2)
  5. Version of Record updated: April 9, 2021 (version 3)
  6. Version of Record updated: April 20, 2021 (version 4)

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.

Metrics

  • 2,442
    Page views
  • 341
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Neuroscience
    Jonathan S Schor et al.
    Research Article

    Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's Disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

    1. Neuroscience
    William T Redman et al.
    Tools and Resources

    The hippocampus consists of a stereotyped neuronal circuit repeated along the septal-temporal axis. This transverse circuit contains distinct subfields with stereotyped connectivity that support crucial cognitive processes, including episodic and spatial memory. However, comprehensive measurements across the transverse hippocampal circuit in vivo are intractable with existing techniques. Here, we developed an approach for two-photon imaging of the transverse hippocampal plane in awake mice via implanted glass microperiscopes, allowing optical access to the major hippocampal subfields and to the dendritic arbor of pyramidal neurons. Using this approach, we tracked dendritic morphological dynamics on CA1 apical dendrites and characterized spine turnover. We then used calcium imaging to quantify the prevalence of place and speed cells across subfields. Finally, we measured the anatomical distribution of spatial information, finding a non-uniform distribution of spatial selectivity along the DG-to-CA1 axis. This approach extends the existing toolbox for structural and functional measurements of hippocampal circuitry.