© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)
aDepartment of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
bRammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
* Corresponding author. Tel.: +49 6221 568476; fax: +49 6221 565515. Email address: Dierk_Thomas{at}med.uni-heidelberg.de
Objective: The human ether-a-go-go-related gene (hERG) encodes the rapid component of the cardiac repolarizing delayed rectifier potassium current, IKr. The direct interaction of the commonly used protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM I) with hERG, KvLQT1/minK, and IKr currents was investigated in this study.
Methods: hERG and KvLQT1/minK channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. In addition, hERG currents in stably transfected human embryonic kidney (HEK 293) cells, native IKr currents and action potentials in isolated guinea pig ventricular cardiomyocytes were recorded using whole-cell patch clamp electrophysiology.
Results: Bisindolylmaleimide I blocked hERG currents in HEK 293 cells and Xenopus oocytes in a concentration-dependent manner with IC50 values of 1.0 and 13.2 µM, respectively. hERG channels were primarily blocked in the open state in a frequency-independent manner. Analysis of the voltage-dependence of block revealed a reduction of inhibition at positive membrane potentials. BIM I caused a shift of –20.3 mV in the voltage-dependence of inactivation. The point mutations tyrosine 652 alanine (Y652A) and phenylalanine 656 alanine (F656A) attenuated hERG current blockade, indicating that BIM I binds to a common drug receptor within the pore region. KvLQT1/minK currents were not significantly altered by BIM I. Finally, 1 µM BIM I reduced native IKr currents by 69.2% and lead to action potential prolongation.
Conclusion: In summary, PKC-independent effects have to be carefully considered when using BIM I as PKC inhibitor in experimental models involving hERG channels and IKr currents.
KEYWORDS Arrhythmia (mechanisms); Hormones; Ion channels; K-channel; Long QT syndrome
Abbreviations: BIM I, bisindolylmaleimide I • hERG, human ether-a-go-go-related gene • PKC, protein kinase C • IKr, rapidly activating component of the delayed rectifier potassium current
1 These authors contributed equally to this work.
Time for primary review 15 days
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