Department of Physiology, Dalian Medical University, Dalian 116044, China.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive 117597, Singapore.
Sci Rep. 2016 Dec 23;6:39320. doi: 10.1038/srep39320.
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 Na1.6 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.
淀粉样前体蛋白（APP）通常与阿尔茨海默病有关，也标志着轴突变性。在最近的研究中，我们证明 APP 在有髓中枢神经系统（CNS）轴突的Ranvier 结（NORs）聚集并与 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。APP 或其包含 VTPEER 基序的细胞内结构域与 Xenopus 卵母细胞中的 Na1.6 钠通道共表达导致峰值钠电流增加，该增加由组成型激活的 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 过表达诱导的 Nav1.6 钠电流的增加。APPT668E（突变 Thr 为 Glu）增加了 Nav1.6 钠电流，而 T668A（突变 Thr 为 Ala）突变则降低了 Nav1.6 钠电流。APP、p35 和 JNK3 敲除小鼠脊髓白质中的 Nav1.6 钠通道的细胞表面表达和脊髓传导速度降低。因此，APP 通过依赖于 APP 在 Thr668 处磷酸化的 Go 偶联 JNK 途径调节 Nav1.6 钠通道。
