Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway.
Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway.
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Neuregulin-1/ErbB4 信号传导通过 Akt/mTOR 途径调节 Kv4.2 介导的瞬时外向 K 电流。
DOI：
10.1152/ajpcell.00041.2013
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
梅岩艾
中科院分区：
文献类型：
--
作者：
梅岩艾
神经调节蛋白-1（NRG-1）是神经营养因子家族的成员，其是神经元的分化、迁移和发育所必需的。NRG-1信号被认为有助于神经元发育和精神分裂症的神经病理学，精神分裂症被认为是一种神经发育障碍。然而，很少有研究探讨NRG-1对电压门控离子通道的作用。在这项研究中，我们报告，NRG-1特异性增加瞬时外向钾电流（IA）在大鼠小脑颗粒神经元（CGNs）的密度在一个时间依赖性的方式，而不改变激活或失活IA通道的特性。IA密度的增加是由IA通道的主要α亚基Kv4.2的蛋白表达增加介导的，最有可能是通过上调翻译。NRG-1对IA密度和Kv4.2表达的影响仅在未成熟神经元中显著。从机制上讲，Akt和哺乳动物雷帕霉素靶蛋白（mTOR）信号传导途径都是增加NRG-1诱导的IA密度和Kv4.2表达所必需的。此外，ErbB4受体的药理学阻断降低了NRG-1对IA密度和Kv4.2诱导的作用。我们的数据首次揭示，NRG-1刺激ErbB4信号通过激活Akt/mTOR信号通路上调K（+）通道蛋白的表达，并在神经元发育和成熟中起重要作用。NRG 1不急性改变大鼠CGN的IA和延迟整流外向（IK），这表明它可能不会通过改变钾通道特性来改变未成熟神经元的兴奋性。
Neuregulin-1 (NRG-1) is a member of a family of neurotrophic factors that is required for the differentiation, migration, and development of neurons. NRG-1 signaling is thought to contribute to both neuronal development and the neuropathology of schizophrenia, which is believed to be a neurodevelopmental disorder. However, few studies have investigated the role of NRG-1 on voltage-gated ion channels. In this study, we report that NRG-1 specifically increases the density of transient outward K(+) currents (IA) in rat cerebellar granule neurons (CGNs) in a time-dependent manner without modifying the activation or inactivation properties of IA channels. The increase in IA density is mediated by increased protein expression of Kv4.2, the main α-subunit of the IA channel, most likely by upregulation of translation. The effect of NRG-1 on IA density and Kv4.2 expression was only significant in immature neurons. Mechanistically, both Akt and mammalian target of rapamycin (mTOR) signaling pathways are required for the increased NRG-1-induced IA density and expression of Kv4.2. Moreover, pharmacological blockade of the ErbB4 receptor reduced the effect of NRG-1 on IA density and Kv4.2 induction. Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K(+) channel proteins via activation of the Akt/mTOR signaling pathway and plays an important role in neuronal development and maturation. NRG1 does not acutely change IA and delayed-rectifier outward (IK) of rat CGNs, suggesting that it may not alter excitability of immature neurons by altering potassium channel property.
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