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Neurobiol Dis. 2014 May;65:220-32. doi: 10.1016/j.nbd.2014.01.019. Epub 2014 Feb 7.

GABA(A) receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.

Author information

1
CNC-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, Portugal.
2
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
3
Wallenberg Neuroscience Center, Lund University, 221 84 Lund, Sweden.
4
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal. Electronic address: cbduarte@ci.uc.pt.

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 β3 subunit at serine 408/409. Expression of phospho-mimetic mutant GABA(A)R β3 subunits prevented receptor internalization and protected hippocampal neurons from ischemic cell death. The results show a key role for β3 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.

KEYWORDS:

Brain ischemia; Calpains; GABA(A) receptors; Gephyrin; Neuroprotection; Receptor traffic

PMID:
24513087
DOI:
10.1016/j.nbd.2014.01.019
[Indexed for MEDLINE]

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