Voltage-gated sodium channels are heterotetrameric sodium
selective
ion channels that play a central role in electrical signaling in excitable
cells. With recent advances in structural biology, structures of eukaryotic
sodium channels have been captured in several distinct conformations
corresponding to different functional states. The secondary structure
of the pore lining S6 helices of subunits DI, DII, and DIV has been
captured with both short π-helix stretches and in fully α-helical
conformations. The relevance of these secondary structure elements
for pore gating is not yet understood. Here, we propose that a π-helix
in at least DI-S6, DIII-S6, and DIV-S6 results in a fully conductive
state. On the other hand, the absence of π-helix in either DI-S6
or DIV-S6 yields a subconductance state, and its absence from both
DI-S6 and DIV-S6 yields a nonconducting state. This work highlights
the impact of the presence of a π-helix in the different S6
helices of an expanded pore on pore conductance, thus opening new
doors toward reconstructing the entire conformational landscape along
the functional cycle of Nav Channels and paving the way to the design
of state-dependent modulators.