title: Oxidative neuronal injury. The dark side of ERK1/2.
abstract: The extracellular signal regulated protein kinases (ERK1/2) are essential for normal development and functional plasticity of the central nervous system. However, a growing number of recent studies in models of cerebral ischemia, brain trauma and neurodegenerative diseases implicate a detrimental role for ERK1/2 signaling during oxidative neuronal injury. Neurons undergoing oxidative stress-related injuries typically display a biphasic or sustained pattern of ERK1/2 activation. A variety of potential targets of reactive oxygen species and reactive nitrogen species could contribute to ERK1/2 activation. These include cell surface receptors, G proteins, upstream kinases, protein phosphatases and proteasome components, each of which could be direct or indirect targets of reactive oxygen or nitrogen species, thereby modulating the duration and magnitude of ERK1/2 activation. Neuronal oxidative stress also appears to influence the subcellular trafficking and/or localization of activated ERK1/2. Differences in compartmentalization of phosphorylated ERK1/2 have been observed in diseased or injured human neurons and in their respective animal and cell culture model systems. We propose that differential accessibility of ERK1/2 to downstream targets, which is dictated by the persistent activation of ERK1/2 within distinct subcellular compartments, underlies the neurotoxic responses that are driven by this kinase.
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Room A-516 UPMC Presbyterian, 200 Lothrop Street, Pittsburgh, PA 15213, USA. chu@np.awing.upmc.edu
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.forename: David J
authors.initials: DJ
authors.lastname: Levinthal
authors.forename: Scott M
authors.initials: SM
authors.lastname: Kulich
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Chalovich
authors.forename: Donald B
authors.initials: DB
authors.lastname: DeFranco
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology; D016923:Cell Death; D002467:Cell Nucleus / Q000201:enzymology; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases