Up-regulation of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) contributes to BDNF-enhanced neurotransmitter release
Up-regulation of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) contributes to BDNF-enhanced neurotransmitter release
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DOI：
10.1111/jnc.13226
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发表时间：
2015-11-01
影响因子：
4.7
通讯作者：
Chen, Zhe-Yu
中科院分区：
文献类型：
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作者：
Chen, Bing;Ma, Xin-Liang;Chen, Zhe-Yu
脑源性神经营养因子(BDNF)参与突触前和突触后突触可塑性的调节。然而，BDNF介导的突触前调控的分子机制仍不完全清楚。在这里，我们报道了BDNF处理4h以上可以显著增强培养的海马神经元c-Jun NH2末端激酶相互作用蛋白3(JIP3)的表达。这种增强可以被Trk抑制剂K252a或cAMP反应元件结合蛋白(CREB)抑制剂所阻断。染色质免疫沉淀(ChIP)分析表明，CREB可与JIP3启动子区域结合，BDNF处理可增加这种结合。利用双荧光素酶分析，我们进一步鉴定了JIP3启动子中的cAMP反应元件(Cre)位点。最后，我们发现BDNF上调的JIP3表达参与了BDNF诱导的神经递质释放的调节。综上所述，我们的研究表明，在海马神经元中，BDNF通过激活CREB上调JIP3的表达，从而有助于促进神经递质的释放；因此，我们发现了BDNF调节突触前传递的新机制。
Brain-derived neurotrophic factor (BDNF) has been implicated in the potent modulation of synaptic plasticity at both pre-synaptic and post-synaptic sites. However, the molecular mechanism underlying BDNF-mediated pre-synaptic modulation remains incompletely understood. Here, we report that BDNF treatment for over 4h could significantly enhance the expression of c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) in cultured hippocampal neurons. This enhancement could be blocked by the Trk inhibitor K252a or by a cAMP response element-binding protein (CREB) inhibitor. In addition, chromatin immunoprecipitation (ChIP) assays revealed that CREB could bind with the JIP3 promoter region and theBDNF treatment could increase this binding. Using dual-luciferase assays we further characterized the cAMP response element (CRE) site in the JIP3 promoter. Finally, we found that BDNF-increased JIP3 expression contributes to the BDNF-induced modulation of neurotransmitter release. Together, our studies reveal that in hippocampal neurons BDNF up-regulates JIP3 expression via CREB activation, which contributes to the enhancement of neurotransmitter release; thus, we have identified a novel mechanism that BDNF modulates pre-synaptic transmission.