The Sodium Channel Accessory Subunit Navβ1 Regulates Neuronal Excitability through Modulation of Repolarizing Voltage-Gated K+ Channels

The channel pore-forming alpha 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 Nav beta 1. Voltage-clamp and current-clamp recordings revealed that knockdown of Nav beta 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 Nav beta 1. Biochemical and voltage-clamp experiments further demonstrated that Nav beta 1 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 Nav beta 1 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.