PERK is responsible for the increased phosphorylation of eIF2alpha and the severe inhibition of protein synthesis after transient global brain ischemia.
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 alpha-subunit of eukaryotic initiation factor 2 (eIF2). To address the role of the eIF2alpha 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 eIF2alpha was detected in the non-ischemic brain and its levels were elevated threefold after 10 min of reperfusion. Conversely, there was no phosphorylated eIF2alpha detected in the non-ischemic transgenic mice and there was no sizeable rise in phosphorylated eIF2alpha 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 eIF2alpha, 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 eIF2alpha and the suppression of translation early in reperfusion after transient global brain ischemia.
Department of Emergency Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Cheri R
CR
Owen
Rita
R
Kumar
Peichuan
P
Zhang
Barbara C
BC
McGrath
Douglas R
DR
Cavener
Gary S
GS
Krause
D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D015427:Reperfusion Injury / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D009419:Nerve Tissue Proteins; D019892:eIF-2 Kinase