| Summary: | (1) Background: voltage-gated sodium channels (Na<sub>v</sub>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<sub>v</sub>α) subunit that forms the channel pore and are coupled to one or more auxiliary β (Na<sub>v</sub>β) subunits that modulate the gating to a variable extent. (2) Methods: after performing homology in silico modeling for all nine isoforms (Na<sub>v</sub>1.1α to Na<sub>v</sub>1.9α), the Na<sub>v</sub>α and Na<sub>v</sub>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<sub>v</sub>α subunits. Precisely, loop S5 in domain I forms part of the PPI and assists Na<sub>v</sub>β1 or Na<sub>v</sub>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<sub>v</sub>β1 or Na<sub>v</sub>β3 subunits on the modulation of Na<sub>v</sub>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.
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