Fig. 1.

Structure of voltage-gated sodium channels. (A) A transmembrane folding diagram of the Na_V1.2 channel. Cylinders represent α-helical segments. Bold lines represent the polypeptide chains of each subunit, with a length approximately proportional to the number of amino acid residues in the brain sodium channel subtypes. The extracellular domains of the β1 and β2 subunits are shown as immunoglobulin-like folds. Ψ, sites of probable N-linked glycosylation; P in red, sites of demonstrated protein phosphorylation by protein kinase A (circles) and protein kinase C (diamonds); blue, pore-lining segments; yellow circles, the outer (EEEE) and inner (DEKA) rings of amino residues that form the tetrodotoxin-binding site and ion selectivity filter; green, S1–S4 voltage sensors; h in blue circle, inactivation particle in the inactivation gate loop; blue circles, sites implicated in forming the inactivation gate receptor. ScTx, scorpion toxin. (B) Model of the local anesthetic receptor site in mammalian Na_V1.2 channels. (C) Side view of Na_VAb channels colored according to (A): voltage-sensing module (green); pore module (blue); S4-S5 linker (red). (D) Side view of the ion selectivity filter. Glu177 (purple) interactions with Gln172, Ser178, and the backbone of Ser180 are shown in the far subunit. F_o-F_c omit map, 4.75 σ (blue); putative cations or water molecules (red spheres, ion_EX). Electron-density around Leu176 (gray; F_o-F_c omit map at 1.75 σ) and a putative water molecule is shown (gray sphere). Na⁺-coordination sites: site_HFS, site_CEN, and site_IN. (E) Architecture of the Na_VAb pore: Glu177 side chains (purple) and pore volume (gray). The S5 and S6 segments and P loop from two lateral subunits are shown.