hERG 1a LQT2 C-terminus truncation mutants display hERG 1b-dependent dominant negative mechanisms

Heart Rhythm. 2016 May;13(5):1121-1130. doi: 10.1016/j.hrthm.2016.01.012. Epub 2016 Jan 13.


Background: The human ether-à-go-go-related gene (hERG 1a) potassium channel is critical for cardiac repolarization. hERG 1b, another variant subunit, co-assembles with hERG 1a, modulates channel biophysical properties and plays an important role in repolarization. Mutations of hERG 1a lead to type 2 long QT syndrome (LQT2), and increased risk for fatal arrhythmias. The functional consequences of these mutations in the presence of hERG 1b are not known.

Objective: To investigate whether hERG 1a mutants exert dominant negative gating and trafficking defects when co-expressed with hERG 1b.

Methods: Electrophysiology, co-immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments in HEK293 cells and guinea pig cardiomyocytes were used to assess the mutants on gating and trafficking. Mutations of 1a-G965X and 1a-R1014X, relevant to gating and trafficking were introduced in the C-terminus region.

Results: The hERG 1a mutants when expressed alone did not result in decreased current amplitude. Compared to wild-type hERG 1a currents, 1a-G965X currents were significantly larger, whereas those produced by the 1a-R1014X mutant were similar in magnitude. Only when co-expressed with wild-type hERG 1a and 1b did a mutant phenotype emerge, with a marked reduction in surface expression, current amplitude, and a corresponding positive shift in the V1/2 of the activation curve. Co-immunoprecipitation and FRET assays confirmed association of mutant and wild-type subunits.

Conclusion: Heterologously expressed hERG 1a C-terminus truncation mutants, exert a dominant negative gating and trafficking effect only when co-expressed with hERG 1b. These findings may have potentially profound implications for LQT2 therapy.

Keywords: Cardiomyocytes; Guinea pig; HEK293; I(Kr); KCNH2; LQT2; Potassium channel; Truncation mutants; hERG 1a; hERG 1b.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electrophysiological Phenomena
  • Ether-A-Go-Go Potassium Channels* / genetics
  • Ether-A-Go-Go Potassium Channels* / metabolism
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Long QT Syndrome* / genetics
  • Long QT Syndrome* / physiopathology
  • Mutation
  • Myocytes, Cardiac / metabolism
  • Protein Transport / physiology


  • Ether-A-Go-Go Potassium Channels
  • KCNH1 protein, human

Supplementary concepts

  • Long Qt Syndrome 2