Regulation Mechanism Of S1 Region On HERG Channel Inactivation

The rapid delayed rectifier potassium current(I_kr)produced by human hERG potassium channel is an important ion current in action potential repolarization ofcardiac myocytes,so hERG plays an important role in action potential repolarization of cardiac myocytes.Gating mechanism of hERG has been extensively and deeply studied,but as a part of channel voltage sensing domain,S1 region of channel transmembrane helix is not fully studied.Some studies have shown that mutations in S1 region affect the gating process of hERG channel,but its mechanism is not clear.Therefore,the aim ofthis study is to study the mechanism of S1 region regulating hERG channel gating by point mutation and N-terminal truncation mutation.We found that after the mutation of Y403,W412,and T421 in the S1 region to alanine,not only the channel activation voltage dependence was shifted,but also the inactivation becamefaster.The representative sites Y403 and S631 were selected for double mutation?Y403A-S631A?,and it was found that there was still a rapid inactivation process in the double mutant hERG channel in the absence of C-type inactivation.When the N-terminal conserved region?eag domain?,the unique long-chain amino acid?138-373?of hERG channel and all N-terminal were truncated on the basis ofY403A-S631A double mutation channel,we found that the rapid inactivation of Y403-S631A double mutation channel disappeared after 138-373 amino acid deletion.This indicates that the rapid inactivation of double mutation channels is indeed related to the N-terminal domain of channels.In summary,this study demonstrates that S1 region regulates a process similar to N-type inactivation of hERG channel and acts on the channel through the unique long-chain amino acid?138-373?region of the N-terminal of hERG channel.