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Title: Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway
Authors: Li, S
Wang, X
Ma, Q.-H
Yang, W.-L
Zhang, X.-G
Dawe, G.S 
Xiao, Z.-C
Keywords: amyloid precursor protein
inhibitory guanine nucleotide binding protein
Scn8a protein, mouse
sodium channel Nav1.6
knockout mouse
MAPK signaling
nerve cell
protein processing
Amyloid beta-Protein Precursor
GTP-Binding Protein alpha Subunits, Gi-Go
MAP Kinase Signaling System
Mice, Knockout
NAV1.6 Voltage-Gated Sodium Channel
Protein Processing, Post-Translational
Issue Date: 2016
Citation: Li, S, Wang, X, Ma, Q.-H, Yang, W.-L, Zhang, X.-G, Dawe, G.S, Xiao, Z.-C (2016). Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway. Scientific Reports 6 : 39320. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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 Na v 1.6 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. © 2016 The Author(s).
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep39320
Rights: Attribution 4.0 International
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