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Title: GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia
Authors: Mele, Miranda 
Ribeiro, Luís 
Inácio, Ana R. 
Wieloch, Tadeusz 
Duarte, C. B. 
Keywords: Neuroprotection; GABAA receptors; Brain ischemia; Receptor traffic; Gephyrin; Calpains
Issue Date: 2014
Publisher: Elsevier Inc.
Serial title, monograph or event: Neurobiology of Disease
Volume: 65
Abstract: 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.
DOI: 10.1016/j.nbd.2014.01.019
Rights: openAccess
Appears in Collections:FCTUC Ciências da Vida - Artigos em Revistas Internacionais

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