title: Ankyrin-G directly binds to kinesin-1 to transport voltage-gated Na+ channels into axons.
abstract: Action potentials (APs) propagating along axons require the activation of voltage-gated Na(+) (Nav) channels. How Nav channels are transported into axons is unknown. We show that KIF5/kinesin-1 directly binds to ankyrin-G (AnkG) to transport Nav channels into axons. KIF5 and Nav1.2 channels bind to multiple sites in the AnkG N-terminal domain that contains 24 ankyrin repeats. Disrupting AnkG-KIF5 binding with small interfering RNA or dominant-negative constructs markedly reduced Nav channel levels at the axon initial segment (AIS) and along entire axons, thereby decreasing AP firing. Live-cell imaging showed that fluorescently tagged AnkG or Nav1.2 cotransported with KIF5 along axons. Deleting AnkG in vivo or virus-mediated expression of a dominant-negative KIF5 construct specifically decreased the axonal level of Nav, but not Kv1.2, channels in mouse cerebellum. These results indicate that AnkG functions as an adaptor to link Nav channels to KIF5 during axonal transport before anchoring them to the AIS and nodes of Ranvier.
authors.affiliation: Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Barry
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Jukkola
authors.affiliation: Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Neill
authors.affiliation: Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Gu
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; Departments of Internal Medicine and Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Keerthi Thirtamara
authors.initials: KT
authors.lastname: Rajamani
authors.affiliation: Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA; Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA. Electronic address: gu.49@osu.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Gu
mesh_terms: D000200:Action Potentials; D000818:Animals; D017487:Ankyrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D001665:Binding Sites; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D016547:Kinesins