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 membraneexcitability. 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 Nav&ngr;1 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. [ABSTRACT FROM AUTHOR]