Abstract
(1) Background: voltage-gated sodium channels (Na(v)s) are integral membrane proteins that allow the sodium ion flux into the excitable cells and initiate the action potential. They comprise an α (Na(v)α) subunit that forms the channel pore and are coupled to one or more auxiliary β (Na(v)β) subunits that modulate the gating to a variable extent. (2) Methods: after performing homology in silico modeling for all nine isoforms (Na(v)1.1α to Na(v)1.9α), the Na(v)α and Na(v)β protein-protein interaction (PPI) was analyzed chemometrically based on the primary and secondary structures as well as topological or spatial mapping. (3) Results: our findings reveal a unique isoform-specific correspondence between certain segments of the extracellular loops of the Na(v)α subunits. Precisely, loop S5 in domain I forms part of the PPI and assists Na(v)β1 or Na(v)β3 on all nine mammalian isoforms. The implied molecular movements resemble macroscopic springs, all of which explains published voltage sensor effects on sodium channel fast inactivation in gating. (4) Conclusions: currently, the specific functions exerted by the Na(v)β1 or Na(v)β3 subunits on the modulation of Na(v)α gating remain unknown. Our work determined functional interaction in the extracellular domains on theoretical grounds and we propose a schematic model of the gating mechanism of fast channel sodium current inactivation by educated guessing.