(A) Key structural features of the Nav channel α-subunit. The four internally homologous domains, DI-IV, are colour-coded, with the S0 and transmembrane helices, S1–6, voltage-sensing domain (VSD), pore domain (PD), C-terminal domain and intracellular DIII-DIV linker region as indicated. (B) Cryo-EM structures of human Nav1.5 (PDB: 7dtc) and human Nav1.4 (PDB: 6agf) in top view and human Nav1.5 in side view. Domains colour-coded as in (A). The intracellular DIII-DIV linker is shown in the side view in light grey.