Two-stage electro–mechanical coupling of a K(V) channel in voltage-dependent activation

In voltage-gated potassium (K(V)) channels, the voltage-sensing domain (VSD) undergoes sequential activation from the resting state to the intermediate state and activated state to trigger pore opening via electro–mechanical (E–M) coupling. However, the spatial and temporal details underlying E–M coupling remain elusive. Here, utilizing K(V)7.1’s unique two open states, we report a two-stage E–M coupling mechanism in voltage-dependent gating of K(V)7.1 as triggered by VSD activations to the intermediate and then activated state. When the S4 segment transitions to the intermediate state, the hand-like C-terminus of the VSD-pore linker (S4-S5L) interacts with the pore in the same subunit. When S4 then proceeds to the fully-activated state, the elbow-like hinge between S4 and S4-S5L engages with the pore of the neighboring subunit to activate conductance. This two-stage hand-and-elbow gating mechanism elucidates distinct tissue-specific modulations, pharmacology, and disease pathogenesis of K(V)7.1, and likely applies to numerous domain-swapped K(V) channels.