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

Rita Kumar, Salman Azam, Jonathan M. Sullivan, Cheri Owen, Douglas R. Cavener, Peichuan Zhang, David Ron, Heather P. Harding, Jane Jane Chen, Anping Han, Blaine C. White, Gary S. Krause, Donald J. DeGracia

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1418-1421
Number of pages4
JournalJournal of neurochemistry
Volume77
Issue number5
DOIs
StatePublished - Jun 21 2001

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Kumar, R., Azam, S., Sullivan, J. M., Owen, C., Cavener, D. R., Zhang, P., Ron, D., Harding, H. P., Chen, J. J., Han, A., White, B. C., Krause, G. S., & DeGracia, D. J. (2001). Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK. Journal of neurochemistry, 77(5), 1418-1421. https://doi.org/10.1046/j.1471-4159.2001.00387.x