During voltage-dependent activation, the voltage-sensing domain (VSD) of Kv channels activates in a stepwise manner from the resting state to an intermediate state before reaching the activated state, which then trigger pore opening via VSD-pore coupling. However, the spatial and temporal details underlying the VSD-pore coupling remain elusive. Leveraging the unique two open states, intermediate open (IO) and activated open (AO) states, of the KCNQ1 (Kv7.1) channel, here we report a two-stage ‘‘Hand-and-Elbow’’ VSD-pore coupling mechanism as triggered by the two-steps VSD activation. When the S4 segment moves to the intermediate state, the hand-like C-terminus of the S4-S5L interacts with its own pore to open the channel in IO; When S4 further proceeds on to the activated state, the elbow-like hinge at S4 and S4-S5L engages with the neighboring pore to open the channel in AO. This new VSD-pore coupling mechanism spatially and temporally dissects when, where, and how the VSD activation is coupled to the PD opening, and is well-conserved for domain-swapped ion channels. 

kv channel,Gating mechanism,VSD-pore coupling