Selectivity filter modalities and rapid inactivation of the hERG1 channel

Williams E. Miranda, Kevin R. DeMarco, Jiqing Guo, Henry J. Duff, Igor Vorobyov, Colleen E. Clancy, Sergei Yu Noskov

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The human ether-á-go-go–related gene (hERG1) channel conducts small outward K+ currents that are critical for cardiomyocyte membrane repolarization. The gain-of-function mutation N629D at the outer mouth of the selectivity filter (SF) disrupts inactivation and K+-selective transport in hERG1, leading to arrhythmogenic phenotypes associated with long-QT syndrome. Here, we combined computational electrophysiology with Markov state model analysis to investigate how SF-level gating modalities control selective cation transport in wild-type (WT) and mutant (N629D) hERG1 variants. Starting from the recently reported cryogenic electron microscopy (cryo-EM) open-state channel structure, multiple microseconds-long molecular-dynamics (MD) trajectories were generated using different cation configurations at the filter, voltages, electrolyte concentrations, and force-field parameters. Most of the K+ permeation events observed in hERG1-WT simulations occurred at microsecond timescales, influenced by the spontaneous dehydration/rehydration dynamics at the filter. The SF region displayed conductive, constricted, occluded, and dilated states, in qualitative agreement with the well-documented flickering conductance of hERG1. In line with mutagenesis studies, these gating modalities resulted from dynamic interaction networks involving residues from the SF, outer-mouth vestibule, P-helices, and S5–P segments. We found that N629D mutation significantly stabilizes the SF in a state that is permeable to both K+ and Na+, which is reminiscent of the SF in the nonselective bacterial NaK channel. Increasing the external K+ concentration induced “WT-like” SF dynamics in N629D, in qualitative agreement with the recovery of flickering currents in experiments. Overall, our findings provide an understanding of the molecular mechanisms controlling selective transport in K+ channels with a nonconventional SF sequence.

Original languageEnglish (US)
Pages (from-to)2795-2804
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number6
DOIs
StatePublished - Feb 11 2020

Keywords

  • Human ether-á-go-go channel
  • Ion channels
  • Long-QT syndrome
  • Molecular dynamics

ASJC Scopus subject areas

  • General

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