title: Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway.
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 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.
authors.affiliation: 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.
authors.forename: Shao
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian 116044, China.|The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical College, Kunming 650031, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive 117597, Singapore.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive 117597, Singapore.|Neurobiology and Ageing Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore, 28 Medical Drive 117456, Singapore.|Singapore Institute for Neurotechnology (SINAPSE), Centre for Life Sciences, National University of Singapore, 28 Medical Drive 117456, Singapore.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Dawe
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical College, Kunming 650031, China.|Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006624:Hippocampus / Q000502:physiology; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D014981:Xenopus
chemical_list: D016564:Amyloid beta-Protein Precursor; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go