Blockade of HERG K+ channel by an antihistamine drug brompheniramine requires the channel binding within the S6 residue Y652 and F656

Sang Joon Park, Ki Suk Kim, Eun Joo Kim

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

A number of clinically used drugs block delayed rectifier K+ channels and prolong the duration of cardiac action potentials associated with long QT syndrome. This study investigated the molecular mechanisms of voltage-dependent inhibition of human ether-a-go-go-related gene (HERG) delayed rectifier K+ channels expressed in HEK-293 cells by brompheniramine, an antihistamine. Brompheniramine inhibited HERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC50) value of 1.7 μm at 0 mV. A block of HERG current by brompheniramine was enhanced by progressive membrane depolarization and showed significantly negative shift in voltage-dependence of channel activation. Inhibition of HERG current by brompheniramine showed time-dependence. The S6 residue HERG mutant Y652A and F656C largely reduced the blocking potency of HERG current. These results indicate that brompheniramine mainly inhibited the HERG potassium channel through the residue Y652 and F656 and these residues may be an obligatory determinant in inhibition of HERG current for brompheniramine.

Original languageEnglish
Pages (from-to)104-111
Number of pages8
JournalJournal of Applied Toxicology
Volume28
Issue number2
DOIs
StatePublished - Mar 2008

Keywords

  • Antihistamine
  • Brompheniramine
  • Cardiac action potential duration
  • HERG potassium channel
  • Long QT syndrome

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