Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant

Ehab Al Moubarak, Yihong Zhang, Chunyun Du, Oliver Hanington, Stephen C Harmer, Christopher E Dempsey, Jules C Hancox*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Citations (Scopus)
113 Downloads (Pure)

Abstract

The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the ability of phenanthrene to interact with hERG (human Ether-à-go-go-Related Gene) encoded Kv11.1 K+ channels, which play a central role in human ventricular repolarization. Pharmacological inhibition of hERG can be proarrhythmic. Whole-cell patch clamp recordings of hERG current (IhERG) were made from HEK293 cells expressing wild-type (WT) and mutant hERG channels. WT IhERG1a was inhibited by phenanthrene with an IC50 of 17.6 ± 1.7 µM, whilst IhERG1a/1b exhibited an IC50 of 1.8 ± 0.3 µM. WT IhERG block showed marked voltage and time dependence, indicative of dependence of inhibition on channel gating. The inhibitory effect of phenanthrene was markedly impaired by the attenuated inactivation N588K mutation. Remarkably, mutations of S6 domain aromatic amino acids (Y652, F656) in the canonical drug binding site did not impair the inhibitory action of phenanthrene; the Y652A mutation augmented IhERG block. In contrast, the F557L (S5) and M651A (S6) mutations impaired the ability of phenanthrene to inhibit IhERG, as did the S624A mutation below the selectivity filter region. Computational docking using a cryo-EM derived hERG structure supported the mutagenesis data. Thus, phenanthrene acts as an inhibitor of the hERG K+ channel by directly interacting with the channel, binding to a distinct site in the channel pore domain.

Original languageEnglish
Pages (from-to)7899-7914
Number of pages16
JournalCellular and Molecular Life Sciences
Volume78
Issue number23
Early online date2 Nov 2021
DOIs
Publication statusE-pub ahead of print - 2 Nov 2021

Bibliographical note

Funding Information:
The authors thank the British Heart Foundation for funding (PG/17/77/33125, PG/17/89/33414, PG/20/10252, FS/19/44/34424, PG/19/26/34302) and Dr John Incardona for helpful discussion and comments on the manuscript.

Funding Information:
This work was funded by the British Heart Foundation: PG/17/77/33125, PG/17/89/33414, PG/20/10252, FS/19/44/34424, PG /19/26/34302.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Hydrocarbon
  • KCNH2
  • PAH
  • Phenanthrene
  • Pollutant
  • Potassium channel

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