title: Amyloid precursor protein enhances Nav1.6 sodium channel cell surface expression.
abstract: Amyloid precursor protein (APP) is commonly associated with Alzheimer disease, but its physiological function remains unknown. Nav1.6 is a key determinant of neuronal excitability in vivo. Because mouse models of gain of function and loss of function of APP and Nav1.6 share some similar phenotypes, we hypothesized that APP might be a candidate molecule for sodium channel modulation. Here we report that APP colocalized and interacted with Nav1.6 in mouse cortical neurons. Knocking down APP decreased Nav1.6 sodium channel currents and cell surface expression. APP-induced increases in Nav1.6 cell surface expression were Go protein-dependent, enhanced by a constitutively active Go protein mutant, and blocked by a dominant negative Go protein mutant. APP also regulated JNK activity in a Go protein-dependent manner. JNK inhibition attenuated increases in cell surface expression of Nav1.6 sodium channels induced by overexpression of APP. JNK, in turn, phosphorylated APP. Nav1.6 sodium channel surface expression was increased by T668E and decreased by T668A, mutations of APP695 mimicking and preventing Thr-668 phosphorylation, respectively. Phosphorylation of APP695 at Thr-668 enhanced its interaction with Nav1.6. Therefore, we show that APP enhances Nav1.6 sodium channel cell surface expression through a Go-coupled JNK pathway.
authors.affiliation: From the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, the Neurobiology and Ageing Programme, Life Sciences Institute and Singapore Institute for Neurotechnology (SINAPSE), Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore 117456.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: From the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, the Neurobiology and Ageing Programme, Life Sciences Institute and Singapore Institute for Neurotechnology (SINAPSE), Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore 117456.
authors.forename: Francis Chee Kuan
authors.initials: FC
authors.lastname: Tan
authors.affiliation: the Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical College, Kunming 650031, China, and the Shunxi-Monash Immune Regeneration and Neuroscience Laboratories, Department of Anatomy and Developmental Biology, Monash University, Clayton, Melbourne, Victoria 3800, Australia zhicheng.xiao@monash.edu.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
authors.affiliation: From the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, the Neurobiology and Ageing Programme, Life Sciences Institute and Singapore Institute for Neurotechnology (SINAPSE), Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore 117456, gavindawe@nus.edu.sg.
authors.forename: Gavin S
authors.initials: GS
authors.lastname: Dawe
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002462:Cell Membrane / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004594:Electrophysiology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D062557:NAV1.6 Voltage-Gated Sodium Channel; D034741:RNA, Small Interfering; C100681:SCN8A protein, human; D048670:MAP Kinase Kinase 4
keywords: Amyloid Precursor Protein (APP); Cell Surface Expression; Duolink; G Protein; Go Protein; JNK; Membrane Protein; Nav1.6 Sodium Channels; Sodium Channel; Trafficking