Chemometric Models of Differential Amino Acids at the Navα and Navβ Interface of Mammalian Sodium Channel Isoforms.

Fernando Villa-Diaz,Susana Lopez-Nunez,Jordan E Ruiz-Castelan,Eduardo Marcos Salinas-Stefanon,Thomas Scior

doi:10.3390/molecules25153551

Fernando Villa-Diaz, Susana Lopez-Nunez + Show 3 more

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https://doi.org/10.3390/molecules25153551

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Abstract

(1) Background: voltage-gated sodium channels (Navs) are integral membrane proteins that allow the sodium ion flux into the excitable cells and initiate the action potential. They comprise an α (Navα) subunit that forms the channel pore and are coupled to one or more auxiliary β (Navβ) subunits that modulate the gating to a variable extent. (2) Methods: after performing homology in silico modeling for all nine isoforms (Nav1.1α to Nav1.9α), the Navα and Navβ 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 Navα subunits. Precisely, loop S5 in domain I forms part of the PPI and assists Navβ1 or Navβ3 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 Navβ1 or Navβ3 subunits on the modulation of Navα 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.

Highlights

IntroductionConcerning the voltage-gated sodium channels (Nav s), a plethora of genes, their reading frames, expression patterns and functions have been reported for various organisms ranging from prokaryotic to eukaryotic cells
The interface concerned the residues of extracellular loops in close contact with the Nav β1 or Nav β3 subunits
Thanks to the chemometric analysis, we formulated a model for fast inactivation of the Nav α pore gating modulated by the presence of either Nav β1 or

Summary

Introduction

Concerning the voltage-gated sodium channels (Nav s), a plethora of genes, their reading frames, expression patterns and functions have been reported for various organisms ranging from prokaryotic to eukaryotic cells. We treat the isoforms of ion channels in vertebrates with their greater gene complexities [1,2]. The Nav complex generally consists of a central α (Nav α) subunit with the channel pore that is encoded by SCN1A to SCN5A (Nav 1.1α to Nav 1.5α, respectively) and SCN8A to SCN11A The nine isoforms of the Nav α subunit are expressed in specific tissue patterns and exhibit differences in gating behavior that adapts them to different physiological functions [3,4,5,6].

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