title: The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels.
abstract: The channel pore-forming α subunit Kv4.2 is a major constituent of A-type (I(A)) potassium currents and a key regulator of neuronal membrane excitability. Multiple mechanisms regulate the properties, subcellular targeting, and cell-surface expression of Kv4.2-encoded channels. In the present study, shotgun proteomic analyses of immunoprecipitated mouse brain Kv4.2 channel complexes unexpectedly identified the voltage-gated Na⁺ channel accessory subunit Navβ1. Voltage-clamp and current-clamp recordings revealed that knockdown of Navβ1 decreases I(A) densities in isolated cortical neurons and that action potential waveforms are prolonged and repetitive firing is increased in Scn1b-null cortical pyramidal neurons lacking Navβ1. Biochemical and voltage-clamp experiments further demonstrated that Navβ1 interacts with and increases the stability of the heterologously expressed Kv4.2 protein, resulting in greater total and cell-surface Kv4.2 protein expression and in larger Kv4.2-encoded current densities. Together, the results presented here identify Navβ1 as a component of native neuronal Kv4.2-encoded I(A) channel complexes and a novel regulator of I(A) channel densities and neuronal excitability.
authors.affiliation: Department of Developmental Biology, Washington University Medical School, St. Louis, Missouri 63110, USA.
authors.forename: Céline
authors.initials: C
authors.lastname: Marionneau
authors.forename: Yarimar
authors.initials: Y
authors.lastname: Carrasquillo
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Norris
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Lori L
authors.initials: LL
authors.lastname: Isom
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Link
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001703:Biophysics; D019921:Biotinylation; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004558:Electric Stimulation; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D051672:Shal Potassium Channels / Q000172:deficiency / Q000378:metabolism*; D015222:Sodium Channels / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; C524974:Scn1b protein, mouse; D051672:Shal Potassium Channels; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; C485184:enhanced green fluorescent protein; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D003513:Cycloheximide