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Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway

机译:淀粉样前体蛋白通过Go偶联JNK途径调节Nav1.6钠通道电流

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摘要

Amyloid precursor protein (APP), commonly associated with Alzheimer’s disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go-coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668.
机译:通常与阿尔茨海默氏病有关的淀粉样前体蛋白(APP)也标志着轴突变性。在最近的研究中,我们证明APP聚集在有髓中枢神经系统(CNS)轴突的Ranvier(NORs)节点上,并与Nav1.6相互作用。然而,APP的生理功能仍然未知。在这项研究中,我们描述了APP敲除海马神经元中钠电流密度降低。在非洲爪蟾卵母细胞中APP或其包含VTPEER母题的细胞内结构域与Nav1.6钠通道的共表达导致峰值钠电流增加,其通过组成型活性Go突变体增强,并被显性负突变体阻断。 JNK和CDK5抑制剂减弱了APP过表达引起的Nav1.6钠电流的增加。 Nav1.6钠电流分别由APPT668E(突变为Thr突变为Glu)增加和由T668A(突变为Thr突变为ALa)降低。在APP,p35和JNK3基因敲除小鼠中,脊髓白质中Nav1.6钠通道的细胞表面表达和脊髓传导速度降低。因此,APP通过Go偶联的JNK途径调节Nav1.6钠通道,这取决于Thr668处APP的磷酸化。

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