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

Abstract

Voltage-gated, sodium ion-selective channels (Na V ) generate electrical signals contributing to the upstroke of the action potential in animals. Na V s are also found in bacteria and are members of a larger family of tetrameric voltagegated channels that includes Ca V s, K V s, and Na V s. Prokaryotic Na V s likely emerged from a homotetrameric Ca 2+ -selective voltage-gated progenerator, and later developed Na + selectivity independently. The Na V 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 V pore, but it is unknown whether they can functionally interact with prokaryotic Na V channels. Herein, we report that the eukaryotic Na V β1-subunit isoform interacts with and enhances the surface expression as well as the voltage-dependent gating properties of the bacterial Na V , NaChBac in Xenopus 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 V structures highlighted the presence of a conserved fold, which could support interactions with the β-subunit. Our the 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.

Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome

“…NaVb1 is a promiscuous and multifunctional protein that (1) potentiates channel activity of the pore-forming voltagegated sodium channel a subunits, [43][44][45][46] (2) functions as a chaperone of sodium channel a subunits from the intracellular pool to the neuronal membrane, 47 (3) interacts with and modulates the activity of voltage-gated potassium channels, [48][49][50] and (4) acts as a cell adhesion molecule to enhance neurite outgrowth. 51 A population of NaVb1 subunits are localized at the axon initial segment, 52 as is NaV1.1.…”

Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels

“…In addition, CiNav1a was not affected by TipE. These findings are surprising given that it has been reported that the bacterial Nav channel can also be modified by mammalian β subunit ( 42 ). To explore why mammalian Nav1 β subunits fail to influence CiNav1a functions, we predicted a structure of CiNav1a bound to β1 by homology modeling (SWISS-MODEL) ( 8 , 43 , 44 ) based on cryo-EM structure of human Nav1.2–β2 complex (Protein Data Bank [PDB] ID: 6J8E ) and electric eel EeNav1.4–β1 complex (PDB ID: 5XSY ) ( 9 ).…”

Computational Investigation of Voltage-Gated Sodium Channel β3 Subunit Dynamics

“…At this stage, it remains unclear as to whether the site of binding is consistent between α subunits or indeed whether the binding interactions for β1 will be the same for β3 (Zhu et al, 2017). Interestingly, it was recently reported that the human β1 subunit can also interact with the bacterial NaChBac channel (Molinarolo et al, 2018) although the mode of interaction was not discussed.…”