Document Detail


Activation of stimulatory heterotrimeric G proteins increases glutathione and protects neuronal cells against oxidative stress.
MedLine Citation:
PMID:  14511129     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oxidative glutamate toxicity in the neuronal cell line HT22 is a model for cell death by oxidative stress, where an excess of extracellular glutamate inhibits import of cystine, a building block of the antioxidant glutathione. The subsequent decrease in glutathione then leads to the accumulation of reactive oxygen species (ROS) and programmed cell death. We used pharmacological compounds known to interact with heterotrimeric G-protein signalling and studied their effects on cell survival, morphology, and intracellular events that ultimately lead to cell death. Cholera toxin and phorbol esters were most effective and prevented cell death through independent pathways. Treating HT22 cells with cholera toxin attenuated the glutamate-induced accumulation of ROS and calcium influx. This was, at least in part, caused by an increase in glutathione due to improved uptake of cystine mediated by the induction of the glutamate/cystine-antiporter subunit xCT or, additionally, by the up-regulation of the antiapoptotic protein Bcl-2. Gs activation also protected HT22 cells from hydrogen peroxide or inhibition of glutathione synthesis by buthionine sulfoximine, and immature cortical neurones from oxidative glutamate toxicity. Thus, this pathway might be more generally implicated in protection from neuronal death by oxidative stress.
Authors:
Jan Lewerenz; Julia Letz; Axel Methner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  87     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-09-26     Completed Date:  2003-11-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  522-31     Citation Subset:  IM    
Affiliation:
Research Group Protective Signalling, Zentrum für Molekulare Neurobiologie and Department of Neurology, University Hospital Hamburg, Hamburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Transport System y+*
Animals
Carrier Proteins / genetics,  metabolism
Cell Death / drug effects
Cell Line
Cholera Toxin / pharmacology
Cyclic AMP / metabolism
GTP-Binding Protein alpha Subunits, Gs / drug effects,  metabolism*
Gene Expression Regulation / drug effects
Glutamic Acid / toxicity
Glutathione / metabolism*
Hippocampus / cytology
Mice
Neurons / cytology,  drug effects,  metabolism*
Neuroprotective Agents / pharmacology
Oxidative Stress / drug effects,  physiology*
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Signal Transduction / drug effects,  physiology
Tetradecanoylphorbol Acetate / pharmacology
Chemical
Reg. No./Substance:
0/Amino Acid Transport System y+; 0/Carrier Proteins; 0/Neuroprotective Agents; 0/Proto-Oncogene Proteins c-bcl-2; 0/Slc7a11 protein, mouse; 16561-29-8/Tetradecanoylphorbol Acetate; 56-86-0/Glutamic Acid; 60-92-4/Cyclic AMP; 70-18-8/Glutathione; 9012-63-9/Cholera Toxin; EC 3.6.5.1/GTP-Binding Protein alpha Subunits, Gs

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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