GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia
Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibrium and neuronal death, but the molecular mechanisms involved are not fully understood. Here we report a downregulation of GABAA receptor (GABAAR...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-05-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114000333 |
| _version_ | 1818352049609244672 |
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| author | Miranda Mele Luís Ribeiro Ana R. Inácio Tadeusz Wieloch Carlos B. Duarte |
| author_facet | Miranda Mele Luís Ribeiro Ana R. Inácio Tadeusz Wieloch Carlos B. Duarte |
| author_sort | Miranda Mele |
| collection | DOAJ |
| description | Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibrium and 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 GABAAR was 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. |
| first_indexed | 2024-12-13T18:47:27Z |
| format | Article |
| id | doaj.art-b665a26886ee4d448e102070dff635cd |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T18:47:27Z |
| publishDate | 2014-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-b665a26886ee4d448e102070dff635cd2022-12-21T23:35:02ZengElsevierNeurobiology of Disease1095-953X2014-05-0165220232GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemiaMiranda Mele0Luís Ribeiro1Ana R. Inácio2Tadeusz Wieloch3Carlos B. Duarte4CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3030-789 Coimbra, PortugalCNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, PortugalWallenberg Neuroscience Center, Lund University, 221 84 Lund, SwedenWallenberg Neuroscience Center, Lund University, 221 84 Lund, SwedenCNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal; Corresponding author at: Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. Fax: +351 239822776.Cerebral ischemia is characterized by an early disruption of GABAergic neurotransmission contributing to an imbalance of the excitatory/inhibitory equilibrium and 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 GABAAR was 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.http://www.sciencedirect.com/science/article/pii/S0969996114000333NeuroprotectionGABAA receptorsBrain ischemiaReceptor trafficGephyrinCalpains |
| spellingShingle | Miranda Mele Luís Ribeiro Ana R. Inácio Tadeusz Wieloch Carlos B. Duarte GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia Neurobiology of Disease Neuroprotection GABAA receptors Brain ischemia Receptor traffic Gephyrin Calpains |
| title | 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_short | 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 |
| topic | Neuroprotection GABAA receptors Brain ischemia Receptor traffic Gephyrin Calpains |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114000333 |
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