Schematic of the membrane topology of Nav α and β subunits. a Nav α subunits have four homologous (DI–DIV) domains, each of which has six transmembrane segments; the voltage-sensing S4 segment in each domain is red and the two (S5 and S6) transmembrane domains contributing to the pore are brown. The inactivation gate (grey) in the DIII–DIV linker and the Nav channel transmembrane accessory (β) subunits, Navβ1–Navβ4, are also shown. Navβ2 and Navβ4 (green) form covalent disulfide bonds with Nav α subunits, whereas Navβ1 and Navβ3 (blue) interact non-covalently with Nav α subunits. Binding sites for additional Nav channel interacting proteins, including AnkyrinG (purple) in the DII–DIII cytosolic linker and iFGF14 (blue) in the C-terminus, are also indicated. b The 24 transmembrane spanning segments of a single Nav α subunit assemble to form an Na+ selective pore (brown)