Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: Implications for mammalian target of rapamycin signaling
Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: Implications for mammalian target of rapamycin signaling
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DOI：
10.1111/j.1471-4159.2005.03466.x
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发表时间：
2005-12-01
影响因子：
4.7
通讯作者：
Takei, N
中科院分区：
文献类型：
--
作者：
Inamura, N;Nawa, H;Takei, N
研究脑源性神经营养因子（BDNF）对皮层神经元翻译伸长的影响及其信号机制。通过测量核糖体传递时间，BDNF增加了大约两倍的延伸率。bdnf加速伸长被雷帕霉素抑制，暗示雷帕霉素的哺乳动物靶点（mTOR）。为了探索这些影响的机制，我们研究了导致神经元中翻译延伸激活的蛋白质磷酸化级联反应。BDNF增加了真核细胞延伸因子1A （eEF1A）的磷酸化，降低了eEF2的磷酸化。雷帕霉素抑制BDNF改变的eEF2磷酸化水平，而雷帕霉素或有丝分裂原活化蛋白激酶（MEK）抑制剂PD98059不影响eEF1A磷酸化。BDNF诱导eEF2激酶（Ser366）磷酸化，并降低其激酶活性。所有这些事件都被雷帕霉素抑制。此外，mTOR siRNA降低mTOR水平达50%，抑制bdnf诱导的延长率增强和eEF2磷酸化降低。这些结果强烈表明BDNF通过激活mTOR-eEF2通路来增强翻译延伸。
The effects and signaling mechanisms of brain-derived neurotrophic factor (BDNF) on translation elongation were investigated in cortical neurons. BDNF increased the elongation rate approximately twofold, as determined by measuring the ribosomal transit time. BDNF-accelerated elongation was inhibited by rapamycin, implicating the mammalian target of rapamycin (mTOR). To explore the mechanisms underlying these effects, we examined the protein phosphorylation cascades that lead to the activation of translation elongation in neurons. BDNF increased eukaryote elongation factor 1A (eEF1A) phosphorylation and decreased eEF2 phosphorylation. Whereas eEF2 phosphorylation levels altered by BDNF were inhibited by rapamycin, eEF1A phosphorylation was not affected by rapamycin or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. BDNF induced phosphorylation of eEF2 kinase (Ser366), as well as decreased its kinase activity. All these events were inhibited by rapamycin. Furthermore, mTOR siRNA, which reduced mTOR levels up to 50%, inhibited the BDNF-induced enhancement in elongation rate and decrease in eEF2 phosphorylation. These results strongly suggest that BDNF enhances translation elongation through the activation of the mTOR-eEF2 pathway.