title: Regulation of c-Jun N-terminal kinase activation in hydrogen peroxide induced neurotoxicity.
abstract: C-Jun N-terminal kinase 1 and 2 (JNK1/2) have been shown to be transiently activated and involved in neurotoxicity. We searched for possible upstream molecules, which are responsible for the regulation of hydrogen peroxide-(H2O2) induced JNK1/2 activation and JNK1/2-mediated apoptotic-like cell death in cultured rat cortical neurons. The results showed that JNK1/2 activation (monitored by anti-diphosphorylated JNK1/2 antibody) was largely prevented by elimination of extracellular Ca2+ or blockage of NMDA-receptors (NMDA-R), and was weakly but significantly decreased by blockage of L-type voltage-gated calcium channel (L-VGCC); furthermore, JNK1/2 activation was largely prevented by inhibition of Ca2+/calmodulin-dependent protein kinase-II (CaMKII) and protein-tyrosine kinases (PTK). We also found that H2O2-induced apoptotic-like cell death was partially prevented by elimination of extracellular Ca2+, or by inhibition of NMDA-R, L-VGCC, PTK and CaMKII, respectively. The above results suggest that in H2O2-induced neurotoxicity, JNK1/2 activation is mainly mediated by NMDA-R and L-VGCC. Consequently, PTK and CaMKII are critical intermediaries in JNK1/2 activation and are mainly responsible for JNK1/2-mediated apoptotic-like cell death.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, Jinagsu 221002, People's Republic of China. wwang@ion.ac.cn
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Hou
authors.forename: Can
authors.initials: C
authors.lastname: Gao
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zong
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D006861:Hydrogen Peroxide / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000633:toxicity*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D006861:Hydrogen Peroxide; D048056:Mitogen-Activated Protein Kinase 9; D011505:Protein-Tyrosine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium