hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: a possible mechanism for long QT syndrome

J Gen Physiol. 2011 Dec;138(6):581-92. doi: 10.1085/jgp.201110683.


Human ether-á-go-go-related gene (hERG) potassium channels are critical for cardiac action potential repolarization. Cardiac hERG channels comprise two primary isoforms: hERG1a, which has a regulatory N-terminal Per-Arnt-Sim (PAS) domain, and hERG1b, which does not. Isolated, PAS-containing hERG1a N-terminal regions (NTRs) directly regulate NTR-deleted hERG1a channels; however, it is unclear whether hERG1b isoforms contain sufficient machinery to support regulation by hERG1a NTRs. To test this, we constructed a series of PAS domain-containing hERG1a NTRs (encoding amino acids 1-181, 1-228, 1-319, and 1-365). The NTRs were also predicted to form from truncation mutations that were linked to type 2 long QT syndrome (LQTS), a cardiac arrhythmia disorder associated with mutations in the hERG gene. All of the hERG1a NTRs markedly regulated heteromeric hERG1a/hERG1b channels and homomeric hERG1b channels by decreasing the magnitude of the current-voltage relationship and slowing the kinetics of channel closing (deactivation). In contrast, NTRs did not measurably regulate hERG1a channels. A short NTR (encoding amino acids 1-135) composed primarily of the PAS domain was sufficient to regulate hERG1b. These results suggest that isolated hERG1a NTRs directly interact with hERG1b subunits. Our results demonstrate that deactivation is faster in hERG1a/hERG1b channels compared to hERG1a channels because of fewer PAS domains, not because of an inhibitory effect of the unique hERG1b NTR. A decrease in outward current density of hERG1a/hERG1b channels by hERG1a NTRs may be a mechanism for LQTS.

Publication types

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

MeSH terms

  • Ether-A-Go-Go Potassium Channels / chemistry
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / genetics
  • Long QT Syndrome / genetics
  • Long QT Syndrome / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Transfection


  • Ether-A-Go-Go Potassium Channels
  • KCNH1 protein, human
  • Peptides
  • Protein Isoforms