Blocking of the Human Ether-a-go-go-Related Gene Channel by Imatinib Mesylate

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  • Dong Qian
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Fu Xiao-xing
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Du Li-li
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Zhao Ning
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Xia Cheng-kun
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Yu Kun-wu
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Cheng Long-xian
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Du Yi-mei
    Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

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  • Blocking of the Human Ether-à-go-go-Related Gene Channel by Imatinib Mesylate

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Imatinib mesylate (IM), a widely prescribed powerful tyrosine kinase inhibitor, has been associated with increased risk of heart failure and is known to induce cell apoptosis and death in isolated cardiomyocytes. In addition to acquired long QT syndrome, pharmacological inhibition of human ether-à-go-go-related gene (HERG) channel has been reported to involve in apoptosis. The present study was undertaken to characterize the biophysical properties of IM on HERG and the molecular determinants of HERG blockade using mutant channels (Y652A and F656A). Wild type (WT) and mutant HERG channels were expressed in HEK-293 cells and Xenopus oocytes and the currents (IHERG) were measured using patch-clamp and two-microelectrode voltage-clamp techniques. IM inhibited WT IHERG in a concentration-dependent manner with an IC50 of 19.51±2.50 µmol/L and 44.76±1.54 µmol/L in HEK-293 cells and Xenopus oocytes, respectively. The IM-induced inhibition of WT IHERG followed a voltage- and time-dependent manner. The blockade was enhanced by further activation of currents, which were in accordance with an open-channel blockade. The V1/2 for steady-state activation shifted from −15.48±1.21 to –26.66±2.98 mV (p<0.05, n=6). The inactivation kinetics and voltage dependence of steady-state inactivation of the WT HERG channel were not significantly altered by IM. Two S6 domain mutants, F652A and Y656A, attenuated IM-induced inhibition of WT IHERG. Therefore, IM preferentially blocked the open HERG channel through F652 and Y656, providing a molecular mechanism for the cardiac side effects during the clinical administration of IM.

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