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hERG channel trafficking: novel targets in drug-induced long QT syndrome

A Dennis1, L Wang, X Wan

  • 1Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44109, U.S.A.

Biochemical Society Transactions
|October 25, 2007
PubMed

Insights

Drug-induced long QT syndrome (LQTS) can arise from direct hERG channel block or impaired trafficking. Awareness of trafficking defects is crucial for preventing cardiac events.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Cardiology
  • Drug Safety

Background:

  • The hERG (human ether-a-go-go-related gene) channel is critical for cardiac repolarization.
  • Direct hERG channel blockade by drugs causes acquired LQTS, leading to arrhythmias.
  • A novel mechanism of acquired LQTS involves drug-induced defects in hERG channel trafficking.

Purpose of the Study:

  • To highlight the significance of hERG trafficking defects in drug-induced cardiotoxicity.
  • To identify therapeutic compounds that inhibit hERG trafficking.
  • To emphasize the need for improved drug safety assays detecting trafficking issues.

Main Methods:

  • Review of existing literature on hERG channel function and drug interactions.
  • Identification of compounds affecting hERG trafficking through safety screening and case studies.
  • Analysis of mechanisms by which drugs impair hERG channel surface expression.

Main Results:

  • Several drugs, including Hsp90 inhibitors (geldanamycin), arsenic trioxide, pentamidine, probucol, and fluoxetine, reduce hERG currents by inhibiting trafficking.
  • These trafficking defects can lead to acquired LQTS and potentially fatal arrhythmias.
  • Conventional safety assays may not detect this novel form of cardiotoxicity.

Conclusions:

  • Drug-induced hERG trafficking defects represent a significant, often undetected, cause of acquired LQTS.
  • Increased awareness and improved screening methods for trafficking defects are essential for pharmaceutical safety.
  • Addressing hERG trafficking issues will enhance the safety of therapeutic compounds and reduce adverse cardiac events.

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