NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression.
NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression.
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DOI：
10.1016/j.neuropharm.2015.03.017
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发表时间：
2016-02
影响因子：
4.7
通讯作者：
Liu SJ
中科院分区：
文献类型：
--
作者：
Bender CL;Yang Q;Sun L;Liu SJ
神经元活动可以改变真核细胞延伸因子2（eEF 2）的磷酸化状态，从而调节蛋白质合成。这被认为是一种突触可塑性形式的潜在机制，涉及突触AMPA型谷氨酸受体表达的变化。钙/钙调蛋白依赖性eEF 2激酶对eEF 2的磷酸化降低了eEF 2的活性，这可以通过常用的eEF 2激酶抑制剂NH 125来防止。在这里，我们发现10 μM NH 125增加了小鼠小脑星状细胞中含有GluA 2的突触受体的表达，并且这被蛋白质合成抑制剂阻止。然而，10 μM的NH 125也降低了CPEB 3的水平，CPEB 3是一种已知与GluA 2 mRNA结合并抑制GluA 2（也称为GluR 2）合成的蛋白质。相反，低浓度的NH 125降低了peEF 2水平，但不改变CPEB 3表达，也未能增加突触GluA 2受体。选择性eEF 2激酶抑制剂A-484954可降低peEF 2的水平，而不改变CPEB 3的表达。这表明减少peEF 2不会导致CPEB 3水平降低，也不足以增加GluA 2合成。因此，10 μM的NH 125通过不依赖于抑制eEF 2激酶的机制降低CPEB 3水平并促进GluA 2翻译。因此，NH 125并不总是通过选择性抑制eEF 2激酶来改变蛋白质合成，并且应谨慎解释NH 125对mRNA翻译的影响。
Neuronal activity can alter the phosphorylation state of eukaryotic elongation factor 2 (eEF2) and thereby regulates protein synthesis. This is thought to be the underlying mechanism for a form of synaptic plasticity that involves changes in the expression of synaptic AMPA type glutamate receptors. Phosphorylation of eEF2 by Ca/calmodulin-dependent eEF2 kinase reduces the activity of eEF2, and this is prevented by a commonly used eEF2 kinase inhibitor, NH125. Here we show that 10 μM NH125 increased the expression of synaptic GluA2-containing receptors in mouse cerebellar stellate cells and this was prevented by a protein synthesis inhibitor. However NH125 at 10 μM also reduced the level of CPEB3, a protein that is known to bind to GluA2 mRNA and suppress GluA2 (also known as GluR2) synthesis. In contrast, a low concentration of NH125 lowered the peEF2 level, but did not alter CPEB3 expression and also failed to increase synaptic GluA2 receptors. A selective eEF2 kinase inhibitor, A-484954, decreased the level of peEF2, without changing the expression of CPEB3. This suggests that reducing peEF2 does not lead to a decrease in CPEB3 levels and is not sufficient to increase GluA2 synthesis. Thus NH125 at 10 μM reduced the level of CPEB3, and promoted GluA2 translation via a mechanism independent of inhibition of eEF2 kinase. Therefore NH125 does not always alter protein synthesis via selective inhibition of eEF2 kinase and the effects of NH125 on translation of mRNAs should be interpreted with caution.