The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels

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,...

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Bibliographic Details
Published in:The Journal of neuroscience 2012-04, Vol.32 (17), p.5716-5727
Main Authors: Marionneau, Céline, Carrasquillo, Yarimar, Norris, Aaron J, Townsend, R Reid, Isom, Lori L, Link, Andrew J, Nerbonne, Jeanne M
Format: Article
Language:English
Subjects:
Analysis of Variance
Animals
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Biophysics
Biotinylation
Cell Line, Transformed
Cerebral Cortex - cytology
Cycloheximide - pharmacology
Electric Stimulation
Endocytosis - drug effects
Endocytosis - genetics
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Immunoprecipitation
Luminescent Proteins - genetics
Luminescent Proteins - metabolism
Mass Spectrometry
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurons - drug effects
Neurons - physiology
Patch-Clamp Techniques
Protein Synthesis Inhibitors - pharmacology
Proteomics
Receptors, Transferrin - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Shal Potassium Channels - deficiency
Shal Potassium Channels - metabolism
Sodium Channels - deficiency
Sodium Channels - metabolism
Transfection
Voltage-Gated Sodium Channel beta-1 Subunit
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/jneurosci.6450-11.2012