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

Version 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

  • 3,259
    Page views
  • 418
    Downloads
  • 17
    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

Share this article

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

Further reading

    1. Neuroscience
    Daniel R Schonhaut, Aditya M Rao ... Michael J Kahana
    Research Article Updated

    Memory formation depends on neural activity across a network of regions, including the hippocampus and broader medial temporal lobe (MTL). Interactions between these regions have been studied indirectly using functional MRI, but the bases for interregional communication at a cellular level remain poorly understood. Here, we evaluate the hypothesis that oscillatory currents in the hippocampus synchronize the firing of neurons both within and outside the hippocampus. We recorded extracellular spikes from 1854 single- and multi-units simultaneously with hippocampal local field potentials (LFPs) in 28 neurosurgical patients who completed virtual navigation experiments. A majority of hippocampal neurons phase-locked to oscillations in the slow (2–4 Hz) or fast (6–10 Hz) theta bands, with a significant subset exhibiting nested slow theta × beta frequency (13–20 Hz) phase-locking. Outside of the hippocampus, phase-locking to hippocampal oscillations occurred only at theta frequencies and primarily among neurons in the entorhinal cortex and amygdala. Moreover, extrahippocampal neurons phase-locked to hippocampal theta even when theta did not appear locally. These results indicate that spike-time synchronization with hippocampal theta is a defining feature of neuronal activity in the hippocampus and structurally connected MTL regions. Theta phase-locking could mediate flexible communication with the hippocampus to influence the content and quality of memories.

    1. Developmental Biology
    2. Neuroscience
    Sergi Llambrich, Birger Tielemans ... Greetje Vande Velde
    Research Article

    Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.