Induction of Bcl-2 by functional regulation of G-protein coupled receptors protects from oxidative glutamate toxicity by increasing glutathione

Glutamate treatment depletes hippocampal HT22 cells of glutathione, which renders the cells incapable to reduce reactive oxygen species and ultimately cumulates in cell death by oxidative stress. HT22 cells resistant to glutamate displayed increased phosphorylation of cAMP-response-element binding (...

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Bibliographic Details
Published in:Free radical research 2006-11, Vol.40 (11), p.1113-1123
Main Authors: Sahin, Mert, Saxena, Ambrish, Joost, Patrick, Lewerenz, Jan, Methner, Axel
Format: Article
Language:English
Subjects:
Bcl-2
Cell Line
Cell Survival
Cyclic AMP Response Element-Binding Protein - metabolism
Dose-Response Relationship, Drug
Glutamates - metabolism
Glutathione - metabolism
Hippocampus - metabolism
HT22 cells
Humans
mGluR
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
oxidative glutamate toxicity
Oxidative Stress
Plasmids - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Receptors, G-Protein-Coupled - metabolism
RNA, Small Interfering - metabolism
VIP
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Summary:Glutamate treatment depletes hippocampal HT22 cells of glutathione, which renders the cells incapable to reduce reactive oxygen species and ultimately cumulates in cell death by oxidative stress. HT22 cells resistant to glutamate displayed increased phosphorylation of cAMP-response-element binding (CREB) and decreased ERK1/2 suggestive of differences in signal transmission. We investigated the amount of candidate G-protein-coupled receptors involved in this resistance and found an increase in mRNA for receptors activated by the vasoactive intestinal peptide VIP (VPAC2, 12.6-fold) and glutamate like the metabotropic glutamate receptor mGlu1 (5.3-fold). Treating cells with VIP and glutamate led to the same changes in protein phosphorylation observed in resistant cells and induced the proto-oncogene Bcl-2. Bcl-2 overexpression protected by increasing the amount of intracellular glutathione and Bcl-2 knockdown by small interfering RNAs (siRNA) increased glutamate susceptibility of resistant cells. Other receptors upregulated in this paradigm might represent useful targets in the treatment of neurological diseases associated with oxidative stress.
ISSN:1071-5762
1029-2470
DOI:10.1080/10715760600838191