Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)

doi:10.1016/j.cardiores.2004.07.023

Cardiovascular Research 2004 64(3):467-476; doi:10.1016/j.cardiores.2004.07.023
© 2004 by European Society of Cardiology

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Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)

Dierk Thomas^a^,*^,1, Bettina C. Hammerling^a^,1, Anna-Britt Wimmer^a^,1, Kezhong Wu^a, Eckhard Ficker^b, Yuri A. Kuryshev^b, Daniel Scherer^a, Johann Kiehn^a, Hugo A. Katus^a, Wolfgang Schoels^a and Christoph A. Karle^a

^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) encodesthe rapid component of the cardiac repolarizing delayed rectifierpotassium current, I_Kr. The direct interaction of the commonlyused protein kinase C (PKC) inhibitor bisindolylmaleimide I(BIM I) with hERG, KvLQT1/minK, and I_Kr currents was investigatedin this study.

Methods: hERG and KvLQT1/minK channels were heterologously expressedin Xenopus laevis oocytes, and currents were measured usingthe two-microelectrode voltage clamp technique. In addition,hERG currents in stably transfected human embryonic kidney (HEK293) cells, native I_Kr currents and action potentials in isolatedguinea pig ventricular cardiomyocytes were recorded using whole-cellpatch clamp electrophysiology.

Results: Bisindolylmaleimide I blocked hERG currents in HEK293 cells and Xenopus oocytes in a concentration-dependent mannerwith IC₅₀ values of 1.0 and 13.2 µM, respectively. hERGchannels were primarily blocked in the open state in a frequency-independentmanner. Analysis of the voltage-dependence of block revealeda reduction of inhibition at positive membrane potentials. BIMI caused a shift of –20.3 mV in the voltage-dependenceof inactivation. The point mutations tyrosine 652 alanine (Y652A)and phenylalanine 656 alanine (F656A) attenuated hERG currentblockade, indicating that BIM I binds to a common drug receptorwithin the pore region. KvLQT1/minK currents were not significantlyaltered by BIM I. Finally, 1 µM BIM I reduced native I_Krcurrents by 69.2% and lead to action potential prolongation.

Conclusion: In summary, PKC-independent effects have to be carefullyconsidered when using BIM I as PKC inhibitor in experimentalmodels involving hERG channels and I_Kr 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 • I_Kr, 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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