title: N-methyl-D-aspartate receptor activation results in regulation of extracellular signal-regulated kinases by protein kinases and phosphatases in glutamate-induced neuronal apototic-like death.
abstract: Extracellular signal-regulated kinases (ERK1/ERK2) have been shown transiently activated and involved in excitotoxicity. We searched for upstream molecules responsible for the regulation of glutamate-induced ERK1/ERK2 activation and ERK1/ERK2-mediated apototic-like death in cultured rat cortical neurons. ERK1/ERK2 activation (monitored by anti-active ERK1/ERK2 antibody) was almost completely prevented by blockage of NMDA receptor (NMDA-R) or elimination of extracellular Ca(2+), but not any other glutamate receptor or L-type voltage-gated Ca(2+) channel. It was prevented largely by inhibition of protein kinase C (PKC), protein-tyrosine kinases (PTK), respectively, but mildly by that of CaM kinase II. Combined inhibition of CaM kinase II (but not PTK) and PKC had an additive effect. Reversion of ERK1/ERK2 activation was largely prevented by inhibition of protein phosphatase (PP) 1 or protein tyrosine phosphatase (PTP). Combined inhibition of PP 1 and PTP had no additive effect. Glutamate-induced apoptotic-like death (determined by DAPI staining) was largely prevented by inhibition of NMDA-R, PKC, CaM kinase II, PTK and MEK1/MEK2 (ERK1/ERK2 kinase), respectively. Combined inhibition of CaM kinase II (but not PKC or PTK) and MEK1/MEK2 had an additive effect. Glutamate-induced apoptotic-like death was promoted by inhibition of PP1 and PTP, respectively. The above results suggested that in glutamate-induced cortical neurotoxicity ERK1/ERK2 activation be mainly mediated by NMDA-R. Subsequently, a pathway dependent on both PKC and PTK was mainly involved, which was also mainly responsible for ERK1/ERK2-mediated apoptotic-like death, and a CaM kinase II-dependent pathway was relatively mildly involved. Reversion of ERK1/ERK2 activation was mainly mediated by a pathway dependent on both PP1 and PTP, which might be involved in the restrain of glutamate-induced neurotoxicity.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiang 221002, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: Z
authors.initials: Z
authors.lastname: Gu
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Jing
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D019319:Okadaic Acid; D018698:Glutamic Acid; D004533:Egtazic Acid; C056723:FG 9041; D016291:Dizocilpine Maleate; D016572:Cyclosporine; D011494:Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D009543:Nifedipine