GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/25639 https://doi.org/10.1016/j.nbd.2014.01.019 |
Resumo: | Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibriumand neuronal death, but the molecular mechanisms involved are not fully understood. Here we report a downregulation of GABAA receptor (GABAAR) expression, affecting both mRNA and protein levels of GABAAR subunits, in hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Similar alterations in the abundance of GABAAR subunits were observed in in vivo brain ischemia. OGD reduced the interaction of surface GABAAR with the scaffold protein gephyrin, followed by clathrin-dependent receptor internalization. Internalization of GABAARwas dependent on glutamate receptor activation and mediated by dephosphorylation of the β3 subunit at serine 408/409. Expression of phospho-mimetic mutant GABAAR β3 subunits prevented receptor internalization and protected hippocampal neurons from ischemic cell death. The results show a key role for β3 GABAAR subunit dephosphorylation in the downregulation of GABAergic synaptic transmission in brain ischemia, contributing to neuronal death. GABAAR phosphorylation might be a therapeutic target to preserve synaptic inhibition in brain ischemia. |
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GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemiaNeuroprotectionGABAA receptorsBrain ischemiaReceptor trafficGephyrinCalpainsCerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibriumand neuronal death, but the molecular mechanisms involved are not fully understood. Here we report a downregulation of GABAA receptor (GABAAR) expression, affecting both mRNA and protein levels of GABAAR subunits, in hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Similar alterations in the abundance of GABAAR subunits were observed in in vivo brain ischemia. OGD reduced the interaction of surface GABAAR with the scaffold protein gephyrin, followed by clathrin-dependent receptor internalization. Internalization of GABAARwas dependent on glutamate receptor activation and mediated by dephosphorylation of the β3 subunit at serine 408/409. Expression of phospho-mimetic mutant GABAAR β3 subunits prevented receptor internalization and protected hippocampal neurons from ischemic cell death. The results show a key role for β3 GABAAR subunit dephosphorylation in the downregulation of GABAergic synaptic transmission in brain ischemia, contributing to neuronal death. GABAAR phosphorylation might be a therapeutic target to preserve synaptic inhibition in brain ischemia.Thiswork was funded by Fundação para a Ciência e a Tecnologia (FCT) and Fundo Europeu para o Desenvolvimento Regional (FEDER) (Pest-C/ SAU/LA0001/2011 and PTDC/NEU-NMC/0198/2012) and the Swedish Research Council (grant no. 8466).Elsevier Inc.2014info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/25639http://hdl.handle.net/10316/25639https://doi.org/10.1016/j.nbd.2014.01.019enghttp://www.sciencedirect.com/science/article/pii/S0969996114000333#Mele, MirandaRibeiro, LuísInácio, Ana R.Wieloch, TadeuszDuarte, C. B.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-05-25T09:38:22Zoai:estudogeral.uc.pt:10316/25639Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:56:03.117940Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
title |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
spellingShingle |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia Mele, Miranda Neuroprotection GABAA receptors Brain ischemia Receptor traffic Gephyrin Calpains |
title_short |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
title_full |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
title_fullStr |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
title_full_unstemmed |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
title_sort |
GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia |
author |
Mele, Miranda |
author_facet |
Mele, Miranda Ribeiro, Luís Inácio, Ana R. Wieloch, Tadeusz Duarte, C. B. |
author_role |
author |
author2 |
Ribeiro, Luís Inácio, Ana R. Wieloch, Tadeusz Duarte, C. B. |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
Mele, Miranda Ribeiro, Luís Inácio, Ana R. Wieloch, Tadeusz Duarte, C. B. |
dc.subject.por.fl_str_mv |
Neuroprotection GABAA receptors Brain ischemia Receptor traffic Gephyrin Calpains |
topic |
Neuroprotection GABAA receptors Brain ischemia Receptor traffic Gephyrin Calpains |
description |
Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibriumand neuronal death, but the molecular mechanisms involved are not fully understood. Here we report a downregulation of GABAA receptor (GABAAR) expression, affecting both mRNA and protein levels of GABAAR subunits, in hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Similar alterations in the abundance of GABAAR subunits were observed in in vivo brain ischemia. OGD reduced the interaction of surface GABAAR with the scaffold protein gephyrin, followed by clathrin-dependent receptor internalization. Internalization of GABAARwas dependent on glutamate receptor activation and mediated by dephosphorylation of the β3 subunit at serine 408/409. Expression of phospho-mimetic mutant GABAAR β3 subunits prevented receptor internalization and protected hippocampal neurons from ischemic cell death. The results show a key role for β3 GABAAR subunit dephosphorylation in the downregulation of GABAergic synaptic transmission in brain ischemia, contributing to neuronal death. GABAAR phosphorylation might be a therapeutic target to preserve synaptic inhibition in brain ischemia. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/25639 http://hdl.handle.net/10316/25639 https://doi.org/10.1016/j.nbd.2014.01.019 |
url |
http://hdl.handle.net/10316/25639 https://doi.org/10.1016/j.nbd.2014.01.019 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
http://www.sciencedirect.com/science/article/pii/S0969996114000333# |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Elsevier Inc. |
publisher.none.fl_str_mv |
Elsevier Inc. |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799133846019506176 |