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Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels

Jijin Lin1, Jun Guo, Hongying Gang

  • 1Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba, Canada R2H 2A6.

Molecular Pharmacology
|June 22, 2005
PubMed

Insights

Drug block of the human Ether-à-go-go-related gene (HERG) potassium channel can cause dangerous heart arrhythmias. This study reveals that while channel inactivation aids drug block, it is not always directly linked, suggesting complex interactions.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cardiology

Background:

  • Medications blocking the human Ether-à-go-go-related gene (HERG) potassium channel can induce long QT syndrome, increasing arrhythmia risk.
  • The inactivated state of HERG channels was previously thought to be preferential for drug binding, but recent evidence challenges this.
  • Understanding drug-HERG interactions is crucial for preventing adverse cardiac events.

Purpose of the Study:

  • To investigate the role of HERG channel inactivation gating in cisapride block.
  • To determine if HERG inactivation is essential for cisapride channel blockade.

Main Methods:

  • Modulation of HERG inactivation using altered extracellular ion concentrations (K+, Cs+).
  • Utilizing mutant HERG channels (F656V, F656M) to assess the role of specific residues.
  • Electrophysiological recordings to measure HERG K+ currents and cisapride block.

Main Results:

  • HERG inactivation facilitated cisapride block of the K+ current.
  • This facilitation was not observed when recording Cs+ currents, decoupling inactivation from block.
  • Cisapride block was not linked to inactivation in F656V and F656M mutant HERG channels.

Conclusions:

  • HERG inactivation facilitates cisapride block, likely by influencing the positioning of Phe-656.
  • The relationship between inactivation and drug block is complex and ion-dependent.
  • Findings contribute to understanding drug-induced arrhythmias and HERG channel function.

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