Proposed localizations of β1 and β3 subunits and their putative interactions with NaV1.5. (A) Location of β1 and β3 according to Zhu et al. (2017), with β1 located between DIII-VSD and DIV-VSD, close to DIV-S4, and β3 located between DII-VSD and DIII-VSD, close to DIII-S4. From these locations, it is easy to imagine how β1 would affect DIV-S4 and β3 would affect DIII-S4. However, it is not clear how β3 affects DIV-S4 from this location. (B–D) Three possible β3 DIV-S4 interactions. (B) The N terminus of β3 reaches over to DIV-S4 and directly affects DIV-S4. (C) Two β3s bind to NaV1.5, one at DIII-S4 and one at DIV-S4. (D) β3 affects DIV-S4 indirectly through an effect via the pore that does not use the S4–S5 linker to S6 coupling. Here shown as a β3-induced rotation of the external end of S5–S6 that is transmitted to DIV-S4 (arrows).
