Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK
Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK
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DOI：
10.1046/j.1471-4159.2001.00387.x
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发表时间：
2001-06-01
影响因子：
4.7
通讯作者：
DeGracia, DJ
中科院分区：
文献类型：
--
作者：
Kumar, R;Azam, S;DeGracia, DJ
全脑缺血再灌注最初导致神经元蛋白质合成受到广泛抑制，这种抑制持续存在于脆弱神经元，这是由于真核细胞起始因子2的a亚单位(elF2α)的磷酸化导致翻译起始受抑所致。为了确定在脑再灌注期间导致elF2α磷酸化[elF2α(P)]的激酶，我们通过双侧颈动脉阻断诱导脑缺血，然后对编码血红素调节的elF2α激酶(HRI)或氨基酸调节的elF2α激酶(GCN2)的基因具有纯合子功能敲除的小鼠进行脑缺血后的评估。在再灌流的野生型小鼠和HRI-/-或GCN2-/-小鼠中观察到elF2α(P)增加了10倍。然而，在所有再灌流组中，RNA依赖的蛋白激酶(PKR)样内质网elF2α激酶(PERK)在SDS-PAGE上显示出与该激酶的激活一致的异构体迁移率移动，这些数据表明，缺血后脑内elF2α(P)的大幅增加不需要HRI或GCN2，并且结合我们先前的报告，再灌注PKR-/-小鼠的脑中产生elF2α(P)，提供了PERK是导致elF2α的激酶的证据。脑缺血后早期的磷酸化。
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 a-subunit of eukaryotic initiation factor 2 (elF2 alpha). To identify kinases responsible for elF2 alpha phosphorylation [elF2 alpha (P)] during brain reperfusion, we induced ischemia by bilateral carotid artery occlusion followed by post-ischemic assessment of brain elF2 alpha (P) in mice with homozygous functional knockouts in the genes encoding the heme-regulated elF2 alpha kinase (HRI), or the amino acid-regulated elF2 alpha kinase (GCN2). A 10-fold increase in elF2 alpha (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 elF2 alpha 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 elF2 alpha (P), and in conjunction with our previous report that elF2 alpha (P) is produced in the brain of reperfused PKR-/- mice, provides evidence that PERK is the kinase responsible for elF2 alpha. phosphorylation in the early post-ischemic brain.