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 α-subunit of eukaryotic initiation factor 2 (eIF2α). To identify kinases responsible for elF2α phosphorylation [eIF2α(P)] during brain reperfusion, we induced ischemia by bilateral carotid artery occlusion followed by post-ischemic assessment of brain eIF2α(P) in mice with homozygous functional knockouts in the genes encoding the heine-regulated eIF2α kinase (HRI), or the amino acid-regulated eIF2α kinase (GCN2). A 10-fold increase in eIF2α(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 eIF2α 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 eIF2α(P), and in conjunction with our previous report that eIF2α(P) is produced in the brain of reperfused PKR-/- mice, provides evidence that PERK is the kinase responsible for eIF2α phosphorylation in the early post-ischemic brain.
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience