Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity
- University of Basel, Switzerland
- University of Copenhagen, Denmark
- University of Montpellier, CNRS, INSERM, France
- 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.
Data availability
For all figures, numerical data that are represented in graphs are provided as source data excel files.
Article and author information
Author details
Diego Fernández-Fernández
Tania Rinaldi Barkat
Kristian Strømgaard
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.
Reviewing Editor
- Moses V Chao, New York University Langone Medical Center, United States
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).
Version history
- Received: July 21, 2022
- Preprint posted: August 4, 2022 (view preprint)
- Accepted: January 22, 2023
- Accepted Manuscript published: January 23, 2023 (version 1)
- Version of Record published: February 10, 2023 (version 2)
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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Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity
eLife 12:e82082.
https://doi.org/10.7554/eLife.82082
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