A caspase-3-like protease is involved in NF-kappaB activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum.
Glutamate receptor stimulation reportedly activates NF-kappaB in vitro and in vivo, although underlying mechanisms remain to be elucidated. Here we evaluated the role of proteases in mediating N-methyl-D-aspartate (NMDA) receptor agonist-induced NF-kappaB activation and apoptosis in rat striatum. The intrastriatal infusion of quinolinic acid (QA, 60 nmol) had no effect on levels of NF-kappaB family proteins, including p65, p50, p52, c-Rel and Rel B. In contrast, QA decreased IkappaB-alpha protein levels by 60% (P<0. 05); other members of the IkappaB family, including IkappaB-beta, IkappaB-gamma, IkappaB-epsilon and Bcl-3, were not altered. The QA-stimulated degradation of IkappaB-alpha was completely blocked by the NMDA receptor antagonist MK-801. QA-induced IkappaB-alpha degradation and NF-kappaB activation were not affected by the proteasome inhibitor MG-132 (1-4 microg). On the other hand, the caspase-3 inhibitor Ac-DEVD.CHO (2-8 microgram) blocked QA-induced IkappaB-alpha degradation in a dose-dependent manner (P<0.05). Ac-DEVD.CHO (4 microgram) also substantially reduced QA-induced NF-kappaB activation (P<0.05), but had no effect on QA-induced AP-1 activation. Furthermore, Ac-DEVD.CHO, but not MG-132, dose-dependently attenuated QA-induced internucleosomal DNA fragmentation. These findings suggest that NF-kappaB activation by NMDA receptor stimulation involves IkappaB-alpha degradation by a caspase-3-like cysteine protease dependent mechanism. Caspase-3 thus appears to contribute to the excitotoxin-induced apoptosis in rat striatal neurons occurring at least partially as a consequence of NF-kappaB activation.
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Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bldg 10, Rm 5C 103, 10 Center Dr. MSC 1406, 20892-1406, Bethesda, MD, USA.
Wang
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Chasea
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TN
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020672:I-kappa B Proteins; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D009707:Nucleosomes; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; D018808:Transcription Factor AP-1; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D000072000:NF-KappaB Inhibitor alpha; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D017378:Quinolinic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde