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PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome

The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca(2+)-activated small con...

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Autores principales: Sun, Jiandong, Liu, Yan, Zhu, Guoqi, Cato, Caleb, Hao, Xiaoning, Qian, Li, Lin, Weiju, Adhikari, Rachana, Luo, Yun, Baudry, Michel, Bi, Xiaoning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299966/
https://www.ncbi.nlm.nih.gov/pubmed/32555345
http://dx.doi.org/10.1038/s41598-020-66790-4
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author Sun, Jiandong
Liu, Yan
Zhu, Guoqi
Cato, Caleb
Hao, Xiaoning
Qian, Li
Lin, Weiju
Adhikari, Rachana
Luo, Yun
Baudry, Michel
Bi, Xiaoning
author_facet Sun, Jiandong
Liu, Yan
Zhu, Guoqi
Cato, Caleb
Hao, Xiaoning
Qian, Li
Lin, Weiju
Adhikari, Rachana
Luo, Yun
Baudry, Michel
Bi, Xiaoning
author_sort Sun, Jiandong
collection PubMed
description The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca(2+)-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.
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spelling pubmed-72999662020-06-18 PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome Sun, Jiandong Liu, Yan Zhu, Guoqi Cato, Caleb Hao, Xiaoning Qian, Li Lin, Weiju Adhikari, Rachana Luo, Yun Baudry, Michel Bi, Xiaoning Sci Rep Article The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca(2+)-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism. Nature Publishing Group UK 2020-06-17 /pmc/articles/PMC7299966/ /pubmed/32555345 http://dx.doi.org/10.1038/s41598-020-66790-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sun, Jiandong
Liu, Yan
Zhu, Guoqi
Cato, Caleb
Hao, Xiaoning
Qian, Li
Lin, Weiju
Adhikari, Rachana
Luo, Yun
Baudry, Michel
Bi, Xiaoning
PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title_full PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title_fullStr PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title_full_unstemmed PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title_short PKA and Ube3a regulate SK2 channel trafficking to promote synaptic plasticity in hippocampus: Implications for Angelman Syndrome
title_sort pka and ube3a regulate sk2 channel trafficking to promote synaptic plasticity in hippocampus: implications for angelman syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299966/
https://www.ncbi.nlm.nih.gov/pubmed/32555345
http://dx.doi.org/10.1038/s41598-020-66790-4
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