Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK

J Neurochem. 2001 Jun;77(5):1418-21. doi: 10.1046/j.1471-4159.2001.00387.x.


Reperfusion after global brain ischemia results initially in a widespread suppression of protein synthesis in neurons, which persists in vulnerable neurons, that is caused by the inhibition of translation initiation as a result of the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha). To identify kinases responsible for eIF2alpha phosphorylation [eIF2alpha(P)] during brain reperfusion, we induced ischemia by bilateral carotid artery occlusion followed by post-ischemic assessment of brain eIF2alpha(P) in mice with homozygous functional knockouts in the genes encoding the heme-regulated eIF2alpha kinase (HRI), or the amino acid-regulated eIF2alpha kinase (GCN2). A 10-fold increase in eIF2alpha(P) was observed in reperfused wild-type mice and in the HRI-/- or GCN2-/- mice. However, in all reperfused groups, the RNA-dependent protein kinase (PKR)-like endoplasmic reticulum eIF2alpha kinase (PERK) exhibited an isoform mobility shift on SDS-PAGE, consistent with the activation of the kinase. These data indicate that neither HRI nor GCN2 are required for the large increase in post-ischemic brain eIF2alpha(P), and in conjunction with our previous report that eIF2alpha(P) is produced in the brain of reperfused PKR-/- mice, provides evidence that PERK is the kinase responsible for eIF2alpha phosphorylation in the early post-ischemic brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Ischemia / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Fibroblasts / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Precipitin Tests
  • Reperfusion Injury / metabolism*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*


  • PERK kinase
  • eIF-2 Kinase