Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity

  1. Pascal Dominic Rem
  2. Vita Sereikaite
  3. Diego Fernández-Fernández
  4. Sebastian Reinartz
  5. Daniel Ulrich
  6. Thorsten Fritzius
  7. Luca Trovo
  8. Salomé Roux
  9. Ziyang Chen
  10. Philippe Rondard
  11. Jean-Philippe Pin
  12. Jochen Schwenk
  13. Bernd Fakler
  14. Martin Gassmann
  15. Tania Rinaldi Barkat
  16. Kristian Strømgaard
  17. Bernhard Bettler  Is a corresponding author
  1. University of Basel, Switzerland
  2. University of Copenhagen, Denmark
  3. University of Montpellier, CNRS, INSERM, France
  4. University of Freiburg, Germany

Abstract

Amyloid-β precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell-surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino-acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

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Article and author information

Author details

  1. Pascal Dominic Rem

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  2. Vita Sereikaite

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  3. Diego Fernández-Fernández

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1431-3705
  4. Sebastian Reinartz

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  5. Daniel Ulrich

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  6. Thorsten Fritzius

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3597-6623
  7. Luca Trovo

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  8. Salomé Roux

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6106-4863
  9. Ziyang Chen

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
  10. Philippe Rondard

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1134-2738
  11. Jean-Philippe Pin

    Institut de Génomique Fonctionnelle, University of Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    No competing interests declared.
  12. Jochen Schwenk

    BrainLinks-BrainTools Cluster of Excellence, University of Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3664-9795
  13. Bernd Fakler

    Institute of Physiology, University of Freiburg, Freiburg, Germany
    Competing interests
    No competing interests declared.
  14. Martin Gassmann

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
  15. Tania Rinaldi Barkat

    Department of Biomedicine, University of Basel, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8650-0986
  16. Kristian Strømgaard

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    Kristian Strømgaard, is a co-founder and a part time employee of Avilex Pharma.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2206-4737
  17. Bernhard Bettler

    Department of Biomedicine, University of Basel, Basel, Switzerland
    For correspondence
    bernhard.bettler@unibas.ch
    Competing interests
    Bernhard Bettler, is a member of the scientific advisory board of Addex Therapeutics, Geneva..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0842-8207

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A-152970)

  • Bernhard Bettler

Brain and Behavior Research Foundation (NARSAD Young Investigator Grant,30389)

  • Sebastian Reinartz

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 animal experiments were approved by the veterinary office of the canton of Basel-Stadt, Switzerland (animal license numbers: 1897_31476 and 3004_34045).

Reviewing Editor

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

Publication history

  1. Received: July 21, 2022
  2. Accepted: January 22, 2023
  3. Accepted Manuscript published: January 23, 2023 (version 1)

Copyright

© 2023, Rem 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. Pascal Dominic Rem
  2. Vita Sereikaite
  3. Diego Fernández-Fernández
  4. Sebastian Reinartz
  5. Daniel Ulrich
  6. Thorsten Fritzius
  7. Luca Trovo
  8. Salomé Roux
  9. Ziyang Chen
  10. Philippe Rondard
  11. Jean-Philippe Pin
  12. Jochen Schwenk
  13. Bernd Fakler
  14. Martin Gassmann
  15. Tania Rinaldi Barkat
  16. Kristian Strømgaard
  17. Bernhard Bettler
(2023)
Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity
eLife 12:e82082.
https://doi.org/10.7554/eLife.82082