Cargando…

GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation

The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropioni...

Descripción completa

Detalles Bibliográficos
Autores principales: Gozdz, Agata, Nikolaienko, Oleksii, Urbanska, Malgorzata, Cymerman, Iwona A., Sitkiewicz, Ewa, Blazejczyk, Magdalena, Dadlez, Michal, Bramham, Clive R., Jaworski, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472658/
https://www.ncbi.nlm.nih.gov/pubmed/28670266
http://dx.doi.org/10.3389/fnmol.2017.00192
_version_ 1783244153800359936
author Gozdz, Agata
Nikolaienko, Oleksii
Urbanska, Malgorzata
Cymerman, Iwona A.
Sitkiewicz, Ewa
Blazejczyk, Magdalena
Dadlez, Michal
Bramham, Clive R.
Jaworski, Jacek
author_facet Gozdz, Agata
Nikolaienko, Oleksii
Urbanska, Malgorzata
Cymerman, Iwona A.
Sitkiewicz, Ewa
Blazejczyk, Magdalena
Dadlez, Michal
Bramham, Clive R.
Jaworski, Jacek
author_sort Gozdz, Agata
collection PubMed
description The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), excitatory synapse strength and dendritic spine morphology. The levels of Arc protein are tightly regulated, and its removal occurs via proteasome-mediated degradation that requires prior ubiquitination. Glycogen synthase kinases α and β (GSK3α, GSKβ; collectively named GSK3α/β) are serine-threonine kinases with abundant expression in the central nervous system. Both GSK3 isozymes are tonically active under basal conditions, but their activity is regulated by intra- and extracellular factors, intimately involved in neuronal activity. Similar to Arc, GSK3α and GSK3β contribute to synaptic plasticity and the structural plasticity of dendritic spines. The present study identified Arc as a GSK3α/β substrate and showed that GSKβ promotes Arc degradation under conditions that induce de novo Arc synthesis. We also found that GSK3α/β inhibition potentiated spine head thinning that was caused by the prolonged stimulation of N-methyl-D-aspartate receptors (NMDAR). Furthermore, overexpression of Arc mutants that were resistant to GSK3β-mediated phosphorylation or ubiquitination resulted in a stronger reduction of dendritic spine width than wildtype Arc overexpression. Thus, GSK3β terminates Arc expression and limits its effect on dendritic spine morphology. Taken together, the results identify GSK3α/β-catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and function.
format Online
Article
Text
id pubmed-5472658
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-54726582017-06-30 GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation Gozdz, Agata Nikolaienko, Oleksii Urbanska, Malgorzata Cymerman, Iwona A. Sitkiewicz, Ewa Blazejczyk, Magdalena Dadlez, Michal Bramham, Clive R. Jaworski, Jacek Front Mol Neurosci Neuroscience The selective and neuronal activity-dependent degradation of synaptic proteins appears to be crucial for long-term synaptic plasticity. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which regulates the synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), excitatory synapse strength and dendritic spine morphology. The levels of Arc protein are tightly regulated, and its removal occurs via proteasome-mediated degradation that requires prior ubiquitination. Glycogen synthase kinases α and β (GSK3α, GSKβ; collectively named GSK3α/β) are serine-threonine kinases with abundant expression in the central nervous system. Both GSK3 isozymes are tonically active under basal conditions, but their activity is regulated by intra- and extracellular factors, intimately involved in neuronal activity. Similar to Arc, GSK3α and GSK3β contribute to synaptic plasticity and the structural plasticity of dendritic spines. The present study identified Arc as a GSK3α/β substrate and showed that GSKβ promotes Arc degradation under conditions that induce de novo Arc synthesis. We also found that GSK3α/β inhibition potentiated spine head thinning that was caused by the prolonged stimulation of N-methyl-D-aspartate receptors (NMDAR). Furthermore, overexpression of Arc mutants that were resistant to GSK3β-mediated phosphorylation or ubiquitination resulted in a stronger reduction of dendritic spine width than wildtype Arc overexpression. Thus, GSK3β terminates Arc expression and limits its effect on dendritic spine morphology. Taken together, the results identify GSK3α/β-catalyzed Arc phosphorylation and degradation as a novel mechanism for controlling the duration of Arc expression and function. Frontiers Media S.A. 2017-06-16 /pmc/articles/PMC5472658/ /pubmed/28670266 http://dx.doi.org/10.3389/fnmol.2017.00192 Text en Copyright © 2017 Gozdz, Nikolaienko, Urbanska, Cymerman, Sitkiewicz, Blazejczyk, Dadlez, Bramham and Jaworski. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Gozdz, Agata
Nikolaienko, Oleksii
Urbanska, Malgorzata
Cymerman, Iwona A.
Sitkiewicz, Ewa
Blazejczyk, Magdalena
Dadlez, Michal
Bramham, Clive R.
Jaworski, Jacek
GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title_full GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title_fullStr GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title_full_unstemmed GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title_short GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation
title_sort gsk3α and gsk3β phosphorylate arc and regulate its degradation
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472658/
https://www.ncbi.nlm.nih.gov/pubmed/28670266
http://dx.doi.org/10.3389/fnmol.2017.00192
work_keys_str_mv AT gozdzagata gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT nikolaienkooleksii gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT urbanskamalgorzata gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT cymermaniwonaa gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT sitkiewiczewa gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT blazejczykmagdalena gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT dadlezmichal gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT bramhamcliver gsk3aandgsk3bphosphorylatearcandregulateitsdegradation
AT jaworskijacek gsk3aandgsk3bphosphorylatearcandregulateitsdegradation