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cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses

GABA(A) and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different rece...

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Detalles Bibliográficos
Autores principales: Niwa, Fumihiro, Patrizio, Angela, Triller, Antoine, Specht, Christian G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926171/
https://www.ncbi.nlm.nih.gov/pubmed/31835170
http://dx.doi.org/10.1016/j.isci.2019.11.013
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author Niwa, Fumihiro
Patrizio, Angela
Triller, Antoine
Specht, Christian G.
author_facet Niwa, Fumihiro
Patrizio, Angela
Triller, Antoine
Specht, Christian G.
author_sort Niwa, Fumihiro
collection PubMed
description GABA(A) and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABA(A)R diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABA(A)R dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes.
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spelling pubmed-69261712019-12-30 cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses Niwa, Fumihiro Patrizio, Angela Triller, Antoine Specht, Christian G. iScience Article GABA(A) and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABA(A)R diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABA(A)R dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes. Elsevier 2019-11-09 /pmc/articles/PMC6926171/ /pubmed/31835170 http://dx.doi.org/10.1016/j.isci.2019.11.013 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Niwa, Fumihiro
Patrizio, Angela
Triller, Antoine
Specht, Christian G.
cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title_full cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title_fullStr cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title_full_unstemmed cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title_short cAMP-EPAC-Dependent Regulation of Gephyrin Phosphorylation and GABA(A)R Trapping at Inhibitory Synapses
title_sort camp-epac-dependent regulation of gephyrin phosphorylation and gaba(a)r trapping at inhibitory synapses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926171/
https://www.ncbi.nlm.nih.gov/pubmed/31835170
http://dx.doi.org/10.1016/j.isci.2019.11.013
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