Phosphorylation of the ot subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus

Phosphorylation of the ot subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus

Author Carnevalli, Larissa S. Autor UNIFESP Google Scholar
Pereira, Catia M. Autor UNIFESP Google Scholar
Jaqueta, Carolina B. Autor UNIFESP Google Scholar
Alves, Viviane S. Autor UNIFESP Google Scholar
Paiva, Vanessa N. Autor UNIFESP Google Scholar
Vattem, Khrishna M. Google Scholar
Wek, Ronald C. Google Scholar
Mello, Luiz Eugenio Araujo de Moraes Autor UNIFESP Google Scholar
Castilho, Beatriz A. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Indiana Univ
Abstract In response to different cellular stresses, a family of protein kinases phosphorylates eIF2 alpha (alpha subunit of eukaryotic initiation factor-2), contributing to regulation of both general and gene-specific translation proposed to alleviate cellular injury or alternatively induce apoptosis. Recently, we reported eIF2 alpha(P) (phosphorylated eIF2 alpha) in the brain during SE (status epilepticus) induced by pilocarpine in mice, an animal model of TLE (temporal lobe epilepsy) [Carnevalli, Pereira, Longo, Jaqueta, Avedissian, Mello and Castilho (2004) Neurosci. Lett. 357, 19 1 194]. We show in the present study that one eIF2 alpha kinase family member, PKR (double-stranded-RNA-dependent protein kinase), is activated in the cortex and hippocampus at 30 min of SE, reflecting the levels of eIF2 alpha(P) in these areas. in PKR-deficient animals subjected to SE, eIF2 alpha phosphorylation was clearly evident coincident with activation of a secondary eIF2 alpha kinase, PEK/PERK (pancreatic eIF2 alpha kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. the extent of eIF2 alpha phosphorylation correlated with the inhibition of protein synthesis in the brain, as determined from polysome profiles. We also found that C57BL/6 mice, which enter SE upon pilocarpine administration but are more resistant to seizure-induced neuronal degeneration, showed very low levels of eIF2 alpha(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2 alpha contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2 alpha phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.
Keywords double-stranded-RNA-dependent protein kinase (PKR)
pilocarpine
status epilepticus
alpha subunit of eukaryotic initiation factor-2 (eIF2 alpha)
temporal lobe epilepsy model
translation initiation
Language English
Date 2006-07-01
Published in Biochemical Journal. London: Portland Press Ltd, v. 397, p. 187-194, 2006.
ISSN 0264-6021 (Sherpa/Romeo, impact factor)
Publisher Portland Press Ltd
Extent 187-194
Origin http://dx.doi.org/10.1042/BJ20051643
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000238699200021
URI http://repositorio.unifesp.br/handle/11600/28987

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