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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia. / Mele, Miranda; Ribeiro, Luís; Inacio, Ana; Wieloch, Tadeusz; Duarte, Carlos B.

I: Neurobiology of Disease, 2014.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

APA

CBE

MLA

Vancouver

Author

RIS

TY - JOUR

T1 - GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia.

AU - Mele, Miranda

AU - Ribeiro, Luís

AU - Inacio, Ana

AU - Wieloch, Tadeusz

AU - Duarte, Carlos B

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1016/j.nbd.2014.01.019

DO - 10.1016/j.nbd.2014.01.019

M3 - Article

JO - Neurobiology of Disease

T2 - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -