Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway.
Neuritin Up-regulates Kv4.2 α-Subunit of Potassium Channel Expression and Affects Neuronal Excitability by Regulating the Calcium-Calcineurin-NFATc4 Signaling Pathway.
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Neuritin 通过调节钙-钙调神经磷酸酶-NFATc4 信号通路上调钾通道表达的 Kv4.2 亚基并影响神经元兴奋性
DOI：
10.1074/jbc.m115.708883
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发表时间：
2016-08-12
期刊：
影响因子：
--
通讯作者：
Mei YA
中科院分区：
文献类型：
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作者：
Yao JJ;Zhao QR;Liu DD;Chow CW;Mei YA
Neuritin是一种重要的神经营养因子，调节神经发育、突触可塑性和神经元存活。阐明neuritin的下游分子信号传导对于neuritin在神经元功能障碍中的潜在治疗应用是重要的。我们以前发现，neuritin上调瞬时钾外向电流（IA）亚基Kv4.2的表达，并增加IA密度，部分通过激活胰岛素受体信号通路。neuritin诱导Kv4.2表达的分子机制仍然难以捉摸。在这里，我们报告的Ca 2 +/钙调神经磷酸酶（CaN）/核因子活化的T细胞（NFAT）C4轴所需的神经素诱导的Kv4.2转录表达和增强IA密度在小脑颗粒神经元。我们发现neuritin升高细胞内Ca 2+，增加Kv4.2表达和IA密度;这种效应对CaN抑制敏感，在Nfatc 4 −/−小鼠中被消除，但在Nfatc 2 −/−小鼠中没有。用neuritin刺激显著增加NFATc 4在小脑颗粒细胞和HeLa细胞中的核积累，其表达IR。此外，NFATc 4被招募到荧光素酶报告基因和染色质免疫沉淀分析检测到的Kv4.2基因启动子位点。更重要的是，从腺相关病毒介导的neuritin过表达后的皮质神经元中获得的数据表明，Nfatc 4 −/−小鼠中神经元兴奋性降低和树突棘形成增加被废除。总之，这些数据证明了CaN/NFATc 4信号通路在神经素调节的神经元功能中不可或缺的作用。
Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca2+/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca2+ and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4−/− mice but not in Nfatc2−/− mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4−/− mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.