Neuritin activates insulin receptor pathway to up-regulate Kv4.2-mediated transient outward K+ current in rat cerebellar granule neurons.
Neuritin activates insulin receptor pathway to up-regulate Kv4.2-mediated transient outward K+ current in rat cerebellar granule neurons.
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DOI：
10.1074/jbc.m112.390260
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发表时间：
2012-11-30
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;Gao XF;Chow CW;Zhan XQ;Hu CL;Mei YA
背景：Neuritin是一种新的神经营养因子。然而，结合neuritin及其下游信号效应物的受体仍不清楚。结果：Neuritin通过激活胰岛素受体途径，增加Kv4.2介导的大鼠小脑颗粒神经元IA。结论：Neuritin可能是胰岛素受体的配体。意义：我们的发现揭示了胰岛素受体在以前未被认识的神经素介导的信号传导中的一个意想不到的作用。neuritin是一种新的神经营养因子，在筛选参与活动依赖性突触可塑性的基因时发现。Neuritin还在神经发育和突触可塑性过程中发挥多种作用。然而，结合neuritin及其下游信号效应物的受体仍不清楚。在这里，我们报告，neuritin特异性地增加大鼠小脑颗粒神经元（CGNs）的瞬时外向K+电流（IA）的密度在时间和浓度依赖性的方式。Neuritin诱导的IA扩增是由IA的主要α亚基Kv4.2的mRNA和蛋白表达增加介导的。CGN暴露于neuritin显著诱导ERK（pERK）、Akt（pAkt）和哺乳动物雷帕霉素靶蛋白（pmTOR）的磷酸化。神经肽诱导的IA和Kv4.2表达增加被ERK、Akt或mTOR抑制剂减弱。出乎意料的是，药理学阻断胰岛素受体，而不是胰岛素样生长因子1受体，消除了神经肽对IA扩增和Kv4.2诱导的作用。事实上，神经肽激活CGN和HeLa中胰岛素受体的下游信号传导效应物。我们的数据首次揭示了胰岛素受体在以前未被识别的神经素介导的信号传导中的意外作用。
Background: Neuritin is a new neurotrophic factor. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Results: Neuritin increases Kv4.2-mediated IA in rat cerebellar granule neurons by activating the insulin receptor pathway. Conclusion: Neuritin may act as a ligand of the insulin receptor. Significance: Our findings reveal an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling. Neuritin is a new neurotrophic factor discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin also plays multiple roles in the process of neural development and synaptic plasticity. The receptors for binding neuritin and its downstream signaling effectors, however, remain unclear. Here, we report that neuritin specifically increases the densities of transient outward K+ currents (IA) in rat cerebellar granule neurons (CGNs) in a time- and concentration-dependent manner. Neuritin-induced amplification of IA is mediated by increased mRNA and protein expression of Kv4.2, the main α-subunit of IA. Exposure of CGNs to neuritin markedly induces phosphorylation of ERK (pERK), Akt (pAkt), and mammalian target of rapamycin (pmTOR). Neuritin-induced IA and increased expression of Kv4.2 are attenuated by ERK, Akt, or mTOR inhibitors. Unexpectedly, pharmacological blockade of insulin receptor, but not the insulin-like growth factor 1 receptor, abrogates the effect of neuritin on IA amplification and Kv4.2 induction. Indeed, neuritin activates downstream signaling effectors of the insulin receptor in CGNs and HeLa. Our data reveal, for the first time, an unanticipated role of the insulin receptor in previously unrecognized neuritin-mediated signaling.