Fig. 8

Suggested model for the inverted gating polarity of K525N&F627Y. a Upon depolarization, WT hERG sequentially forms three states, the closed, the open, and inactivated state. As the membrane potential depolarizes, S4 (yellow) of hERG slides extracellularly and slowly drives the activation gate open (red) via the S4-S5 linker (grey). Channels transit from a closed state into an open state that mediates an outward K⁺ current. Once the membrane potential is higher than 0 mV, S4 further translocates extracellularly, and channels are inactivated. Channels reach the inactivated state that is non-conductive to ions. The non-canonical coupling pathway between the VSD and PD is critical for the hERG channel function. b K525N&F627Y preserves two states of hERG, the open and the inactivated state. When the membrane potential is higher than -70 mV, S4 (yellow) usually sits extracellularly. Channels stay in the inactivated state that is non-conductive to ions. Once the membrane potential hyperpolarizes, S4 would translocate mildly toward the intracellular, and relieve the inactivation gate. Channels transit into a “leaky open” state that mediates an inward K⁺ current