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PERK is responsible for the increased phosphorylation of eIF2α and the severe inhibition of protein synthesis after transient global brain ischemia
Author(s) -
Owen Cheri R.,
Kumar Rita,
Zhang Peichuan,
McGrath Barbara C.,
Cavener Douglas R.,
Krause Gary S.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03276.x
Subject(s) - phosphorylation , elongation factor , eukaryotic initiation factor , forebrain , ischemia , protein kinase a , eif2 , translation (biology) , endoplasmic reticulum , eukaryotic translation elongation factor 1 alpha 1 , genetically modified mouse , transgene , biology , medicine , microbiology and biotechnology , endocrinology , messenger rna , biochemistry , gene , rna , central nervous system , ribosome
Reperfusion after global brain ischemia results initially in a widespread suppression of protein synthesis in neurons that is due to inhibition of translation initiation as a result of the phosphorylation of the α‐subunit of eukaryotic initiation factor 2 (eIF2). To address the role of the eIF2α kinase RNA‐dependent protein kinase‐like endoplasmic reticulum kinase (PERK) in the reperfused brain, transgenic mice with a targeted disruption of the Perk gene were subjected to 20 min of forebrain ischemia followed by 10 min of reperfusion. In wild‐type mice, phosphorylated eIF2α was detected in the non‐ischemic brain and its levels were elevated threefold after 10 min of reperfusion. Conversely, there was no phosphorylated eIF2α detected in the non‐ischemic transgenic mice and there was no sizeable rise in phosphorylated eIF2α levels in the forebrain after ischemia and reperfusion. Moreover, there was a substantial rescue of protein translation in the reperfused transgenic mice. Neither group showed any change in total eIF2α, phosphorylated eukaryotic elongation factor 2 or total eukaryotic elongation factor 2 levels. These data demonstrate that PERK is responsible for the large increase in phosphorylated eIF2α and the suppression of translation early in reperfusion after transient global brain ischemia.