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Intracellular potassium stabilizes human ether-à-go-go-related gene channels for export from endoplasmic reticulum

Lu Wang1, Adrienne T Dennis, Phan Trieu

  • 1Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA.

Molecular Pharmacology
|January 14, 2009
PubMed

Insights

Cardiac glycosides disrupt human ether-à-go-go-related gene (hERG) channel trafficking by inhibiting Na+/K+ pumps, leading to intracellular potassium depletion. This potassium depletion causes a conformational defect in hERG, impairing its cell surface transport.

Area of Science:

  • Cardiology
  • Molecular Pharmacology
  • Cell Biology

Background:

  • Therapeutic compounds can prolong QT interval and cause arrhythmias by disrupting hERG channel trafficking.
  • Cardiac glycosides are a key class of compounds that inhibit hERG trafficking.
  • Previous work linked cardiac glycoside inhibition of hERG trafficking to Na+/K+ pump block.

Purpose of the Study:

  • To elucidate the mechanism coupling Na+/K+ pump inhibition to hERG processing.
  • To investigate the role of intracellular potassium in hERG trafficking.
  • To identify conditions and factors that restore hERG trafficking.

Main Methods:

  • Utilized cardiac glycosides and gramicidin to deplete intracellular potassium in cell models.
  • Assessed hERG trafficking under conditions of potassium depletion and restoration.
  • Investigated the effect of ion permeability, temperature, pharmacological chaperones, and hERG mutations on trafficking.

Main Results:

  • Intracellular potassium depletion, induced by cardiac glycosides or gramicidin, disrupts hERG trafficking.
  • Restoration of hERG trafficking in potassium-depleted cells was achieved by K+ or Rb+ ion permeation, low temperatures, astemizole, or specific hERG mutations.
  • These findings indicate a direct link between intracellular potassium levels and hERG channel conformation.

Conclusions:

  • Cardiac glycosides inhibit hERG trafficking via a mechanism involving intracellular potassium depletion.
  • The study reveals a novel pathway for drug-induced trafficking inhibition mediated by potassium-dependent conformational changes in the hERG channel.
  • Understanding this mechanism is crucial for developing safer therapeutics and managing drug-induced arrhythmias.

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