Cross-kingdom auxiliary subunit modulation of a voltage-gated sodium channel.

Voltage-gated, sodium ion-selective channels (Na) generate electrical signals contributing to the upstroke of the action potential in animals. Nas are also found in bacteria and are members of a larger family of tetrameric voltage-gated channels that includes Cas, Ks, and Nas. Prokaryotic Nas likely emerged from a homotetrameric Ca-selective voltage-gated progenerator, and later developed Na selectivity independently. The Na signaling complex in eukaryotes contains auxiliary proteins, termed beta (β) subunits, which are potent modulators of the expression profiles and voltage-gated properties of the Na pore, but it is unknown whether they can functionally interact with prokaryotic Na channels. Herein, we report that the eukaryotic Naβ1-subunit isoform interacts with and enhances the surface expression as well as the voltage-dependent gating properties of the bacterial Na, NaChBac in oocytes. A phylogenetic analysis of the β-subunit gene family proteins confirms that these proteins appeared roughly 420 million years ago and that they have no clear homologues in bacterial phyla. However, a comparison between eukaryotic and bacterial Na structures highlighted the presence of a conserved fold, which could support interactions with the β-subunit. Our electrophysiological, biochemical, structural, and bioinformatics results suggests that the prerequisites for β-subunit regulation are an evolutionarily stable and intrinsic property of some voltage-gated channels.