Dysfunction of the Unfolded Protein Response During Global

Summary: A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane– bound proteins ATF6, IRE1, and PERK. The authors simul-taneously examined the activation of ATF6, IRE1, and PERK, as well as components of downstream UPR pathways, in the rat brain after reperfusion after a 10-minute cardiac arrest. Al-though ATF6 was not activated, PERK was maximally acti-vated at 10-minute reperfusion, which correlated with maximal eIF2 phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80 % loss of PERK immunostaining in cortex and 50 % loss in brain stem and hippocampus. PERK was degraded in vitro by -calpain. Although inactive IRE1 was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had bee