title: Peroxynitrite modulates the activation of p38 and extracellular regulated kinases in PC12 cells.
abstract: Although peroxynitrite appears to contribute to neuronal dysfunction in several neurodegenerative disorders, little is known about how peroxynitrite affects cellular signaling processes. This study investigated if peroxynitrite affects the mitogen-activated protein kinases, extracellular-regulated kinases 1 and 2 (ERK1/2) and p38. Exposure of PC12 cells to 500 microM peroxynitrite activated ERK1/2 and p38 within 5 min and this was followed by gradual decreases in activation over the next 25 min. Activation of ERK1/2 by peroxynitrite was mediated by activation of the epidermal growth factor (EGF) receptor in a calcium/calmodulin-dependent kinase II- and src family tyrosine kinase-dependent manner, as it was blocked by the selective EGF receptor inhibitor AG1478, by KN62, an inhibitor of calcium/calmodulin-dependent kinase II, and by PP1, a src family tyrosine kinase inhibitor. Activation of p38 by peroxynitrite was independent of the EGF receptor, required activation of calcium/calmodulin-dependent kinase II and src family tyrosine kinases, and was modulated by nerve growth factor (NGF) in a time-dependent manner. Pretreatment with NGF (2 h) attenuated, whereas cotreatment with NGF potentiated, peroxynitrite-induced activation of p38. Thus, peroxynitrite activates ERK1/2 and p38, activation of EGF receptors, calcium/calmodulin-dependent kinase II, and src family tyrosine kinases participate in these signaling responses to peroxynitrite, and peroxynitrite- and NGF-induced signaling activities converge on p38.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Jope
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Song
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009566:Nitrates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D051381:Rats; D020032:Tyrphostins / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D009566:Nitrates; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C039642:peroxynitric acid; D004815:Epidermal Growth Factor; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020932:Nerve Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases