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

Marionneau C, Carrasquillo Y, Norris AJ, Townsend RR, Isom LL, Link AJ, Nerbonne JM
J Neurosci. 2012 32 (17): 5716-27

PMID: 22539834 · PMCID: PMC3347704 · DOI:10.1523/JNEUROSCI.6450-11.2012

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.

MeSH Terms (29)

Analysis of Variance Animals Bacterial Proteins Biophysics Biotinylation Cell Line, Transformed Cerebral Cortex Cycloheximide Electric Stimulation Endocytosis Gene Expression Regulation Green Fluorescent Proteins Humans Immunoprecipitation Luminescent Proteins Mass Spectrometry Mice Mice, Inbred C57BL Mice, Knockout Neurons Patch-Clamp Techniques Protein Synthesis Inhibitors Proteomics Receptors, Transferrin RNA, Small Interfering Shal Potassium Channels Sodium Channels Transfection Voltage-Gated Sodium Channel beta-1 Subunit

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