GABA(A) receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.
Neurobiol Dis
; 65: 220-32, 2014 May.
Article
en En
| MEDLINE
| ID: mdl-24513087
ABSTRACT
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 GABA(A) receptor (GABA(A)R) expression, affecting both mRNA and protein levels of GABA(A)R subunits, in hippocampal neurons subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Similar alterations in the abundance of GABA(A)R subunits were observed in in vivo brain ischemia. OGD reduced the interaction of surface GABA(A)R with the scaffold protein gephyrin, followed by clathrin-dependent receptor internalization. Internalization of GABA(A)R was dependent on glutamate receptor activation and mediated by dephosphorylation of the ß3 subunit at serine 408/409. Expression of phospho-mimetic mutant GABA(A)R ß3 subunits prevented receptor internalization and protected hippocampal neurons from ischemic cell death. The results show a key role for ß3 GABA(A)R subunit dephosphorylation in the downregulation of GABAergic synaptic transmission in brain ischemia, contributing to neuronal death. GABA(A)R phosphorylation might be a therapeutic target to preserve synaptic inhibition in brain ischemia.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores de GABA-B
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Infarto de la Arteria Cerebral Media
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Glucosa
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Hipoxia
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Neurobiol Dis
Asunto de la revista:
NEUROLOGIA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Portugal