A model illustrating the close proximity and interactions among the S3-4 linker (e.g., Y1618), the SS6 pore loop (e.g., W1716), and the internal pore-lining part of S6 (e.g., F1764) in domain 4 of the Na⁺ channel, making a pivotal apparatus for ion permeation, activation-inactivation coupling, and drug binding. (A) The transmembrane segments S3–S6 in domain 4 of the channel are plotted as rectangular cylinders and viewed from the pore. W1716 is adjacent to A1714 in sequence, and thus is most likely located externally to the selectivity filter in the SS6 pore loop. This position could reasonably interact with F1764 of S6 if there is a turn at the junction of SS6 loop and S6 helix. As a result, the S6 helix in the vicinity of F1764 forms a “recess” of the pore. The aromatic residues Y1618, W1716, and F1764 are plotted as yellow dots. Membrane voltage changes move the S4 segment, and thus move the S3-4, S4-5, and S5-6 linkers to contribute to the essential voltage-dependent physiological and pharmacological attributes of the channel. (B) An enlarged picture for the interacting aromatic residues in A. (C) A homology model for the S6 recess of domain 4 in Nav1.2 based on the crystallized structure of the KcsA K⁺ channel pore (done by an online server provided by the Swiss Institute of Bioinformatics: http://swissmodel.expasy.org). Because of the marked difference in the length of the pore loops between these two types of channels, the homology modeling is based on somewhat arbitrary sequence alignment of the key conservative residues of D4SS6 and S6 (marked by green and orange rectangles, respectively) in the Na_v1.2 channel and a subunit in the KcsA channel, with a large portion of pore loop in Nav1.2 deleted (top panel; note the sequence numbering and the arrows indicating W1716 and F1764). In the molecular model (bottom panel), the S5, S6, and S5-S6 linker of domain 4 are shown as space fills and colored gray, orange, and dark green, respectively. A1714 is in light green to mark the possible location of the selectivity filter. The aromatic side chains of W1716 in SS6 and F1764 in S6 are shown in yellow. A carbamazepine molecule could be well docked to a receptor constituted by W1716 and F1764 in the recess region of this model with the Discovery Studio software (Accelyrs Inc.; not depicted). (D) The brown-colored areas illustrate the other part of the channel protein surrounding the aqueous pore region (light blue), which is made by the four SS5-SS6 loops from the four domains (illustrated as the four “walls” making the external part of the pore). W1716 on the SS5-SS6 loop and F1764 on S6 (dotted helix; both residues depicted as yellow phenyl groups) of domain 4 interact to form a recess, which is more readily depicted with an angle of view roughly perpendicular to that in A and B. The anticonvulsant drug (shown as a pink diphenyl motif) presumably binds to its receptor located at the S6 recess with dipole-induced dipole interactions among the phenyl groups of the drug (pink), W1716 and F1764 (both in yellow; the boxed picture). A hydrophobic drug molecule of suitable conformation could even go through the S6 recess and thus traverse the pore without trespassing on the selectivity filter, embodying the long-proposed “hydrophobic” pathway of local anesthetic action on the Na⁺ channel.