title: ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3.
abstract: Our recent studies have shown that extracellular-regulated protein kinase (ERK) promotes cell death in cerebellar granule neurons (CGN) cultured in low potassium. Here we report that the "death" phenotypes of CGN after potassium withdrawal are heterogeneous, allowing the distinction between plasma membrane (PM)-, DNA-, and PM/DNA-damaged populations. These damaged neurons display nuclear condensation that precedes PM or DNA damage. Inhibition of ERK activation either by U0126 or by dominant-negative mitogen-activated protein kinase/ERK kinase (MEK) overexpression results in a dramatic reduction of PM damaged neurons and nuclear condensation. In contrast, overexpression of constitutively active MEK potentiates PM damage and nuclear condensation. ERK-promoted cellular damage is independent of caspase-3. Persistent active ERK translocates to the nucleus, whereas caspase-3 remains in the cytoplasm. Antioxidants that reduced ERK activation and PM damage showed no effect on caspase-3 activation or DNA damage. These data identify ERK as an important executor of neuronal damage involving a caspase-3-independent mechanism.
authors.affiliation: Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 307, 2. OG, D-69120 Heidelberg, Germany. Srinivasa.Subramaniam@urz.uni-heidelberg.de
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Ute
authors.initials: U
authors.lastname: Zirrgiebel
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.forename: Jens
authors.initials: J
authors.lastname: Strelau
authors.forename: Christine
authors.initials: C
authors.lastname: Laliberté
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Klaus
authors.initials: K
authors.lastname: Unsicker
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D011191:Potassium Deficiency / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases