Na_v channel function, family tree, and structural architecture. (A) Evoked action potential recorded from a mouse DRG neuron at room temperature before (black) and after (red) the application of 1 µM TTX. X axis is 30 ms, and y axis is 20 mV. (B) A phylogenetic tree of Na_v channels as well as Shaker obtained using Vector NTI AlignX software. (C) The side view of a signal subunit of the Na_vAb channel homotetramer (Protein Data Bank accession no. 3RVY) in ribbon style is colored from N terminus (blue) to C terminus (red). This view highlights the VSD as a modular four-helix bundle. (D) Side view of the Na_vAb channel with the front VSD and pore domain removed for clarity. For illustrative purposes, Na_vAb is colored according to a pseudotetrameric arrangement expected for eukaryotic Na_v cannels. Representative classes of protein toxins (α, β, and µ), small molecule toxins (TTX), as well select small molecule drugs (lidocaine and benzocaine) are represented with arrows pointing to their presumed canonical binding sites on the channel. (E) Top-view schematic of a eukaryotic Na_v channel with the S3b–S4 region of the VSDs from different domains is highlighted in different colors. The ion-conducting Na⁺ pore is found in the center of this view. (F) A structural top view of the Na_vAb channel colored according to a pseudotetrameric arrangement expected for a eukaryotic Na_v channel (as in D). This subunit coloring highlights the “domain-swapped arrangement” of the VSDs around the PM observed for all voltage-gated ion channels.