Voltage Sensor Movement in the hERG K+ Channel

The critical role of hERG in the maintenance of normal cardiac electrical activity derives from its unusual gating properties: slow channel activation and fast inactivation. To characterize voltage sensor movement associated with slow activation and fast inactivation, we measured gating currents from wild-type and mutant hERG channels. Fast and slow gating components were observed that differed 100-fold in their kinetics. The slow component constituted the majority of gating charge associated with channel opening and accounted for the sluggish rate of hERG activation. Gating currents from an inactivation-deficient mutant (S631A) were indistinguishable from wild-type, despite a +100 mV shift in the voltage dependence of inactivation, suggesting that a small fraction of total gating charge is devoted to the final transitions that inactivate the channel. Ala-scanning mutagenesis in S4 identified residues that perturbed both charge movement and channel opening. Residues in the S4-S5 linker perturbed channel opening without altering charge displacement, suggesting a role for coupling S4 movement to channel opening. Finally, inactivation-sensitive residues localized to a helical face of S4 adjacent to the activation-sensitive residues. We conclude that S4 acts as the voltage sensor for hERG activation and inactivation and that S4 movement is translated to the activation gate via the S4-S5 linker.