1. Structural Biology and Molecular Biophysics
  2. Neuroscience
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Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

  1. Irene Riva
  2. Clarissa Eibl
  3. Rudolf Volkmer
  4. Anna L Carbone  Is a corresponding author
  5. Andrew J R Plested  Is a corresponding author
  1. Humboldt Universität zu Berlin, Germany
  2. Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
Research Article
  • Cited 14
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Cite this article as: eLife 2017;6:e28680 doi: 10.7554/eLife.28680

Abstract

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of γ2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

Article and author information

Author details

  1. Irene Riva

    Institute of Biology,Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Clarissa Eibl

    Institute of Biology,Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Rudolf Volkmer

    Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna L Carbone

    Institute of Biology,Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany
    For correspondence
    carbone@fmp-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrew J R Plested

    Institute of Biology,Cellular Biophysics, Humboldt Universität zu Berlin, Berlin, Germany
    For correspondence
    plested@fmp-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6062-0832

Funding

Deutsche Forschungsgemeinschaft (Fellowship and studentship Cluster of Excellence NeuroCure EXC-257)

  • Anna L Carbone

Austrian Science Fund (Erwin-Schrödinger Postdoctoral Fellowship J3682-B21)

  • Clarissa Eibl

Deutsche Forschungsgemeinschaft (Research Group Dynion FOR 2518)

  • Andrew J R Plested

Deutsche Forschungsgemeinschaft (Heisenberg Professor)

  • Andrew J R Plested

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

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Publication history

  1. Received: May 16, 2017
  2. Accepted: August 28, 2017
  3. Accepted Manuscript published: August 30, 2017 (version 1)
  4. Version of Record published: September 14, 2017 (version 2)

Copyright

© 2017, Riva 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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