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

Larissa S. Carnevalli, Catia M. Pereira, Carolina B. Jaqueta, Viviane S. Alves, Vanessa N. Paiva, Krishna M. Vattem, Ronald C. Wek, Luiz Eugênio A.M. Mello, Beatriz A. Castilho

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21 Scopus citations

Abstract

In response to different cellular stresses, a family of protein kinases phosphorylates eIF2α (α 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 eIF2α(P) (phosphorylated eIF2α) 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, 191-194]. We show in the present study that one eIF2α 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 eIF2α(P) in these areas. In PKR-deficient animals subjected to SE, eIF2α phosphorylation was clearly evident coincident with activation of a secondary eIF2α kinase, PEK/PERK (pancreatic eIF2α kinase/RNA-dependent-protein-kinase-like endoplasmic reticulum kinase), denoting a compensatory mechanism between the two kinases. The extent of eIF2α 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 eIF2α(P) and no inhibition of protein synthesis during SE. These results taken together suggest that PKR-mediated phosphorylation of eIF2α contributes to inhibition of protein synthesis in the brain during SE and that sustained high levels of eIF2α phosphorylation may facilitate ensuing cell death in the most affected areas of the brain in TLE.

Original languageEnglish (US)
Pages (from-to)187-194
Number of pages8
JournalBiochemical Journal
Volume397
Issue number1
DOIs
StatePublished - Jul 1 2006

Keywords

  • α subunit of eukaryotic initiation factor-2 (eIF2α)
  • Double-stranded-RNA-dependent protein kinase (PKR)
  • Pilocarpine
  • Status epilepticus
  • Temporal lobe epilepsy model
  • Translation initiation

ASJC Scopus subject areas

  • Biochemistry

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    Carnevalli, L. S., Pereira, C. M., Jaqueta, C. B., Alves, V. S., Paiva, V. N., Vattem, K. M., Wek, R. C., Mello, L. E. A. M., & Castilho, B. A. (2006). Phosphorylation of the α subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus. Biochemical Journal, 397(1), 187-194. https://doi.org/10.1042/BJ20051643