Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity
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 suff...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82082 |
| _version_ | 1828036744769961984 |
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| author | Pascal Dominic Rem Vita Sereikaite Diego Fernández-Fernández Sebastian Reinartz Daniel Ulrich Thorsten Fritzius Luca Trovo Salomé Roux Ziyang Chen Philippe Rondard Jean-Philippe Pin Jochen Schwenk Bernd Fakler Martin Gassmann Tania Rinaldi Barkat Kristian Strømgaard Bernhard Bettler |
| author_facet | Pascal Dominic Rem Vita Sereikaite Diego Fernández-Fernández Sebastian Reinartz Daniel Ulrich Thorsten Fritzius Luca Trovo Salomé Roux Ziyang Chen Philippe Rondard Jean-Philippe Pin Jochen Schwenk Bernd Fakler Martin Gassmann Tania Rinaldi Barkat Kristian Strømgaard Bernhard Bettler |
| author_sort | Pascal Dominic Rem |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T16:02:04Z |
| format | Article |
| id | doaj.art-f48ea31c4d5245788aa36e87dccbb8c4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T16:02:04Z |
| publishDate | 2023-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f48ea31c4d5245788aa36e87dccbb8c42023-02-10T13:11:45ZengeLife Sciences Publications LtdeLife2050-084X2023-01-011210.7554/eLife.82082Soluble amyloid-β precursor peptide does not regulate GABAB receptor activityPascal Dominic Rem0Vita Sereikaite1Diego Fernández-Fernández2https://orcid.org/0000-0003-1431-3705Sebastian Reinartz3Daniel Ulrich4Thorsten Fritzius5https://orcid.org/0000-0002-3597-6623Luca Trovo6Salomé Roux7https://orcid.org/0000-0002-6106-4863Ziyang Chen8Philippe Rondard9https://orcid.org/0000-0003-1134-2738Jean-Philippe Pin10Jochen Schwenk11https://orcid.org/0000-0003-3664-9795Bernd Fakler12https://orcid.org/0000-0001-7264-6423Martin Gassmann13Tania Rinaldi Barkat14https://orcid.org/0000-0001-8650-0986Kristian Strømgaard15https://orcid.org/0000-0003-2206-4737Bernhard Bettler16https://orcid.org/0000-0003-0842-8207Department of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken, Copenhagen, DenmarkDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandInstitut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, FranceCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken, Copenhagen, DenmarkInstitut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, FranceInstitut de Génomique Fonctionnelle, Université de Montpellier, Montpellier, FranceInstitute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, GermanyInstitute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS Center for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany; Center for Basics in NeuroModulation, Freiburg, GermanyDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandCenter for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken, Copenhagen, DenmarkDepartment of Biomedicine, Pharmazentrum, University of Basel, Basel, SwitzerlandAmyloid-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.https://elifesciences.org/articles/82082GABABG protein-coupled receptorssoluble amyloid-β precursor protein |
| spellingShingle | Pascal Dominic Rem Vita Sereikaite Diego Fernández-Fernández Sebastian Reinartz Daniel Ulrich Thorsten Fritzius Luca Trovo Salomé Roux Ziyang Chen Philippe Rondard Jean-Philippe Pin Jochen Schwenk Bernd Fakler Martin Gassmann Tania Rinaldi Barkat Kristian Strømgaard Bernhard Bettler Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity eLife GABAB G protein-coupled receptors soluble amyloid-β precursor protein |
| title | Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity |
| title_full | Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity |
| title_fullStr | Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity |
| title_full_unstemmed | Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity |
| title_short | Soluble amyloid-β precursor peptide does not regulate GABAB receptor activity |
| title_sort | soluble amyloid β precursor peptide does not regulate gabab receptor activity |
| topic | GABAB G protein-coupled receptors soluble amyloid-β precursor protein |
| url | https://elifesciences.org/articles/82082 |
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