Biphasic activation of apoptosis signal-regulating kinase 1-stress-activated protein kinase 1-c-Jun N-terminal protein kinase pathway is selectively mediated by Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involving oxidative stress following brain ischemia in rat hippocampus.
Stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1/MKK4) was examined in a rat model of global brain ischemia. Western blot assay showed that SEK1 activation was biphasic in CA1 but not CA3/dentate gyrus. The second activation peak (3 days after ischemia) was prevented by pretreatment with l-naphthyl acetyl spermine (Naspm), a channel blocker of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, or N-acetylcysteine (NAC), a free radical scavenger. Concomitantly, the late activation of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal protein kinase (JNK) was also prevented by Naspm or NAC. Moreover, phospho-SEK1 and phospho-JNK co-immunoprecipitated with ASK1 and the bindings peaked at 3 days of reperfusion. Together with previous results, these findings indicate that Ca(2+)-permeable AMPA receptors are important routes to mediate the late activation of ASK1-SEK1-JNK pathway involving oxidative stress in hippocampal CA1 region after ischemia.
Zhang
Quanguang
Q
Research center for Biochemistry and Molecular Biology Xuzhou Medical College, Jiangsu, PR China.
Zhang
Guangyi
G
Meng
Fanjie
F
Tian
Hui
H
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D006624:Hippocampus / Q000378:metabolism*; D015640:Ion Channel Gating; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018091:Receptors, AMPA; C067506:1-naphthylacetylspermine; D013096:Spermine; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D009543:Nifedipine; D002118:Calcium; D000111:Acetylcysteine