Modulation of Voltage-Gated K+ Channels by the Sodium Channel β1 Subunit

Abstract

Voltage-gated sodium (Nav) and potassium (Kv) channels are key components of neuronal electrical excitability. Here we report that Navβ1, an integral subunit of Nav channels, associates with and modulates the biophysical properties of the Kv1 and Kv7 channels, in an isoform-specific manner, but not those of the Kv3 channels. Distinct domains of Navβ1 modulate specific biophysical properties of different Kv channels. Studies with channel chimeras demonstrate that Navβ1-mediated changes in activation kinetics and voltage-dependence of activation require interaction of Navβ1 with the channel's voltage-sensing domain, while changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Navβ1 lying in the crevice between the voltage-sensing and pore domains of Kv channels, making significant contacts with the S1 and S5 segments, and the external loop making significant contacts with outer loops of at least two monomers in the channel. Cross-modulation of Nav and Kv channels by Navβ1 may promote diversity and flexibility in the overall control of cellular excitability and signaling.