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GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.

Mele, Miranda; Ribeiro, Luís; Inacio, Ana LU ; Wieloch, Tadeusz LU and Duarte, Carlos B (2014) In Neurobiology of Disease
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 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 gephrin, followed by clathrin-dependent receptor internalization. Internalization of GABAAR was dependent... (More)
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 gephrin, followed by clathrin-dependent receptor internalization. Internalization of GABAAR was dependent on glutamate receptor activation and mediated by dephosphorylation of β3 at serine 408/409. Expression of phospho-mimetic mutants of 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. (Less)
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published
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Neurobiology of Disease
publisher
Elsevier
external identifiers
  • pmid:24513087
  • wos:000333546300023
  • scopus:84896313006
ISSN
0969-9961
DOI
10.1016/j.nbd.2014.01.019
language
English
LU publication?
yes
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bc77389a-39b8-4ed4-9a31-b1209d358688 (old id 4335036)
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http://www.ncbi.nlm.nih.gov/pubmed/24513087?dopt=Abstract
date added to LUP
2014-03-06 13:04:19
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2017-01-22 04:17:00
@article{bc77389a-39b8-4ed4-9a31-b1209d358688,
  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 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 gephrin, followed by clathrin-dependent receptor internalization. Internalization of GABAAR was dependent on glutamate receptor activation and mediated by dephosphorylation of β3 at serine 408/409. Expression of phospho-mimetic mutants of 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.},
  author       = {Mele, Miranda and Ribeiro, Luís and Inacio, Ana and Wieloch, Tadeusz and Duarte, Carlos B},
  issn         = {0969-9961},
  language     = {eng},
  month        = {02},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.},
  url          = {http://dx.doi.org/10.1016/j.nbd.2014.01.019},
  year         = {2014},
}