Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of DAPK1

  1. Jamie McQueen
  2. Tomas J Ryan
  3. Sean McKay
  4. Katie FM Marwick
  5. Paul S Baxter
  6. Sarah M Carpanini
  7. Thomas M Wishart
  8. Thomas H Gillingwater
  9. Jean C Manson
  10. David JA Wyllie
  11. Seth GN Grant
  12. Barry McColl  Is a corresponding author
  13. Noboru Komiyama
  14. Giles E Hardingham  Is a corresponding author
  1. Edinburgh Medical School, University of Edinburgh, United Kingdom
  2. Trinity College Dublin, Ireland
  3. University of Edinburgh, United Kingdom
  4. The Roslin Institute, United Kingdom
  5. Wellcome Trust Sanger Institute, United Kingdom

Abstract

Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by DAPK1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by DAPK1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg2+ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of DAPK1 or altered Ser-1303 phosphorylation.

Article and author information

Author details

  1. Jamie McQueen

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Tomas J Ryan

    School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  3. Sean McKay

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Katie FM Marwick

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Paul S Baxter

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah M Carpanini

    The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas M Wishart

    University of Edinburgh, The Roslin Institute, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas H Gillingwater

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean C Manson

    The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. David JA Wyllie

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4957-6049
  11. Seth GN Grant

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8732-8735
  12. Barry McColl

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Barry.McColl@roslin.ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0521-9656
  13. Noboru Komiyama

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Giles E Hardingham

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Giles.Hardingham@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7629-5314

Funding

Wellcome (WT088156)

  • Giles E Hardingham

Medical Research Council (MRC_G0902044)

  • Jamie McQueen
  • Sean McKay
  • Paul S Baxter
  • Giles E Hardingham

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

Ethics

Animal experimentation: All experiments using live animals were conducted under the authority of UK Home Office project and personal licences and adhered to regulations specified in the Animals (Scientific Procedures) Act (1986) and Directive 2010/63/EU and were approved by both The Roslin Institute's and the University of Edinburgh's Animal Welfare and Ethics Committees. Experimental design, analysis and reporting followed the ARRIVE guidelines (https://www.nc3rs.org.uk/arrive-guidelines) where possible. Animal experimentation: Animals used in this study were treated in accordance with UK Animal Scientific Procedures Act (1986) . The relevant Home Office project licences are P1351480E and 60/4407, and the use of genetically modified organisms approved by local committee reference SBMS 13_007.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Publication history

  1. Received: April 22, 2016
  2. Accepted: July 17, 2017
  3. Accepted Manuscript published: July 21, 2017 (version 1)
  4. Accepted Manuscript updated: July 26, 2017 (version 2)
  5. Version of Record published: August 4, 2017 (version 3)

Copyright

© 2017, McQueen 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. Jamie McQueen
  2. Tomas J Ryan
  3. Sean McKay
  4. Katie FM Marwick
  5. Paul S Baxter
  6. Sarah M Carpanini
  7. Thomas M Wishart
  8. Thomas H Gillingwater
  9. Jean C Manson
  10. David JA Wyllie
  11. Seth GN Grant
  12. Barry McColl
  13. Noboru Komiyama
  14. Giles E Hardingham
(2017)
Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of DAPK1
eLife 6:e17161.
https://doi.org/10.7554/eLife.17161

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