hERG 1b is critical for human cardiac repolarization

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Abstract
Significance: The 1a subunit of the human ether-à-go-go–related gene (hERG) potassium channel is a critical component of cardiac repolarization and the cornerstone of safety screens for new drug development. A second subunit, 1b, coassembles with 1a and modifies channel gating and drug block sensitivity. Adoption of 1a/1b heteromers as a model of native hERG current, IKr, has been hampered by the absence of direct evidence that 1b contributes to human cardiac repolarization. This study provides the first functional evidence, to our knowledge, that 1a/1b channels rather than homomeric 1a channels mediate repolarization. Because heteromeric and homomeric hERG channels have different pharmacological profiles, these findings have implications for native IKrmodels and hERG-based drug safety tests that help protect against drug-induced sudden cardiac death.
Funding Information
  • HHS | National Institutes of Health (NIH) (T32-HL007936)
  • HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (NHLBI-R01HL081780)
  • HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (NHLBI-HL083121)
  • American Heart Association (AHA) (11SDG5000003)
  • HHS | National Institutes of Health (NIH) (R01 NS081320)

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