Consolidation of object recognition memory requires HRI kinase-dependent phosphorylation of eIF2 in the hippocampus
Consolidation of object recognition memory requires HRI kinase-dependent phosphorylation of eIF2 in the hippocampus
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DOI：
10.1002/hipo.22113
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发表时间：
2013-06-01
期刊：
影响因子：
3.5
通讯作者：
Cammarota, Martin
中科院分区：
文献类型：
--
作者：
Ill-Raga, Gerard;Koehler, Cristiano;Cammarota, Martin
突触蛋白质合成的局部控制对突触可塑性和记忆形成至关重要。然而，在这些过程中，神经递质释放与翻译机制耦合的信号知之甚少。在这里，我们研究了血红素调节抑制剂（HRI）激酶，一种由一氧化氮激活的激酶，磷酸化真核起始因子2 (eIF2)，在物体识别（OR）记忆巩固中的作用。磷酸化的eIF2介导两种相反的翻译作用：大多数mrna的翻译阻滞和在其5非翻译区（5UTRs）中具有特定特征的选定mrna的翻译激活。我们发现，大鼠海马背侧CA1区的HRI激酶激活对于OR记忆的保留是必要的。因此，学习诱导了CA1背侧eIF2磷酸化状态的短暂增加，这一磷酸化状态被HRI激酶抑制剂N-（2,6-二甲基苄基）-6,7-二甲氧基- 2h -[1]苯并呋喃[3,2-c]吡唑-3-胺盐酸（AMI）所消除。p-eIF2的增加与BACE1和激活转录因子4的表达增加有关，这两种蛋白在其mrna中含有eif2应答的5UTRs，在突触可塑性中起关键作用。我们的数据表明，学习促进了eIF2的短暂磷酸化，从而允许通过一个需要HRI激酶激活的过程翻译特定的5utr - mrna。(c) 2013 Wiley Periodicals, Inc.；
Local control of protein synthesis at synapses is crucial for synaptic plasticity and memory formation. However, little is known about the signals coupling neurotransmitter release with the translational machinery during these processes. Here, we studied the involvement of heme-regulated inhibitor (HRI) kinase, a kinase activated by nitric oxide that phosphorylates eukaryotic initiation factor 2 (eIF2), in object recognition (OR) memory consolidation. Phosphorylated eIF2 mediates two opposing effects upon translation: translational arrest of most mRNAs and translational activation of selected mRNAs bearing specific features in their 5untranslated regions (5UTRs). We found that HRI kinase activation in the CA1 region of the dorsal hippocampus is necessary for retention of OR memory in rats. Accordingly, learning induced a transient increase in the phosphorylation state of eIF2 in dorsal CA1 which was abolished by the HRI kinase inhibitor N-(2,6-dimethylbenzyl)-6,7-dimethoxy-2H-[1]benzofuro[3,2-c]pyrazol-3-amine hydrochloride (AMI). The increase in p-eIF2 was associated with increased expression of BACE1 and activating transcription factor 4, two proteins containing eIF2-responsive 5UTRs in their mRNAs that play a key role in synaptic plasticity. Our data suggests that learning promotes the transient phosphorylation of eIF2 to allow for translation of specific 5UTR-mRNAs through a process requiring HRI kinase activation. (c) 2013 Wiley Periodicals, Inc.