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

Research output: Contribution to journalArticle

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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

Fingerprint

Eukaryotic Initiation Factor-2
Brain Ischemia
Endoplasmic Reticulum
Reperfusion
Brain
Phosphotransferases
Phosphorylation
eIF-2 Kinase
Neurons
Gene Knockout Techniques
Gene encoding
Carotid Arteries
Polyacrylamide Gel Electrophoresis
Protein Isoforms
Ischemia
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Kumar, Rita ; Azam, Salman ; Sullivan, Jonathan M. ; Owen, Cheri ; Cavener, Douglas R. ; Zhang, Peichuan ; Ron, David ; Harding, Heather P. ; Chen, Jane Jane ; Han, Anping ; White, Blaine C. ; Krause, Gary S. ; DeGracia, Donald J. / Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK. In: Journal of neurochemistry. 2001 ; Vol. 77, No. 5. pp. 1418-1421.
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title = "Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK",
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.",
author = "Rita Kumar and Salman Azam and Sullivan, {Jonathan M.} and Cheri Owen and Cavener, {Douglas R.} and Peichuan Zhang and David Ron and Harding, {Heather P.} and Chen, {Jane Jane} and Anping Han and White, {Blaine C.} and Krause, {Gary S.} and DeGracia, {Donald J.}",
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Kumar, R, Azam, S, Sullivan, JM, Owen, C, Cavener, DR, Zhang, P, Ron, D, Harding, HP, Chen, JJ, Han, A, White, BC, Krause, GS & DeGracia, DJ 2001, 'Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK', Journal of neurochemistry, vol. 77, no. 5, pp. 1418-1421. https://doi.org/10.1046/j.1471-4159.2001.00387.x

Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK. / Kumar, Rita; Azam, Salman; Sullivan, Jonathan M.; Owen, Cheri; Cavener, Douglas R.; Zhang, Peichuan; Ron, David; Harding, Heather P.; Chen, Jane Jane; Han, Anping; White, Blaine C.; Krause, Gary S.; DeGracia, Donald J.

In: Journal of neurochemistry, Vol. 77, No. 5, 21.06.2001, p. 1418-1421.

Research output: Contribution to journalArticle

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T1 - Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK

AU - Kumar, Rita

AU - Azam, Salman

AU - Sullivan, Jonathan M.

AU - Owen, Cheri

AU - Cavener, Douglas R.

AU - Zhang, Peichuan

AU - Ron, David

AU - Harding, Heather P.

AU - Chen, Jane Jane

AU - Han, Anping

AU - White, Blaine C.

AU - Krause, Gary S.

AU - DeGracia, Donald J.

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Y1 - 2001/6/21

N2 - 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.

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