Inhibition of IkappaBalpha phosphorylation prevents glutamate-induced NF-kappaB activation and neuronal cell death.
NF-kappaB is a nuclear transcription factor involved in the control of fundamental cellular functions including regulation of cell survival. We investigated NF-kappaB activation induced by two opposing modulators of cell viability: IL-1beta and glutamate. We found that IL-1beta activated p50, p65 and c-Rel subunits of NF-kappaB, while glutamate activated only p50 and p65 proteins. Cell stimulation by glutamate, correlated with expression of the pro-apoptotic genes Caspase-3, Caspase-2L and Bax. Conversely, IL-1beta induced the expression of the short anti-apoptotic isoform of Caspase-2. Finally, we analysed the effect of the inhibition of IkappaBalpha degradation on glutamate-induced toxicity by using BAY 11-7082, a selective inhibitor of IkappaBalpha phosphorylation. Our results suggest that BAY 11-7082 preserves neuron viability from the glutamate-mediated injury.
Division of Pharmacology, Department of Biomedical Sciences & Biotechnologies, Brescia, Italy. pizzi@med.unibs.it
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Pizzi
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Sarnico
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Boroni
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Benetti
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Benarese
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Spano
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors; D018698:Glutamic Acid / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D018698:Glutamic Acid