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Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate.
Biol Pharm Bull. 2013; 36(2):268-75.BP

Abstract

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 (I(HERG)) were measured using patch-clamp and two-microelectrode voltage-clamp techniques. IM inhibited WT I(HERG) in a concentration-dependent manner with an IC(50) 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 I(HERG) 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 V(1/2) 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 I(HERG). 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.

Authors+Show Affiliations

Ion Channelopathy Research Center, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23196655

Citation

Dong, Qian, et al. "Blocking of the Human Ether-à-go-go-related Gene Channel By Imatinib Mesylate." Biological & Pharmaceutical Bulletin, vol. 36, no. 2, 2013, pp. 268-75.
Dong Q, Fu XX, Du LL, et al. Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate. Biol Pharm Bull. 2013;36(2):268-75.
Dong, Q., Fu, X. X., Du, L. L., Zhao, N., Xia, C. K., Yu, K. W., Cheng, L. X., & Du, Y. M. (2013). Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate. Biological & Pharmaceutical Bulletin, 36(2), 268-75.
Dong Q, et al. Blocking of the Human Ether-à-go-go-related Gene Channel By Imatinib Mesylate. Biol Pharm Bull. 2013;36(2):268-75. PubMed PMID: 23196655.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blocking of the human ether-à-go-go-related gene channel by imatinib mesylate. AU - Dong,Qian, AU - Fu,Xiao-Xing, AU - Du,Li-Li, AU - Zhao,Ning, AU - Xia,Cheng-Kun, AU - Yu,Kun-Wu, AU - Cheng,Long-Xian, AU - Du,Yi-Mei, Y1 - 2012/11/30/ PY - 2012/12/1/entrez PY - 2012/12/1/pubmed PY - 2013/8/6/medline SP - 268 EP - 75 JF - Biological & pharmaceutical bulletin JO - Biol Pharm Bull VL - 36 IS - 2 N2 - 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 (I(HERG)) were measured using patch-clamp and two-microelectrode voltage-clamp techniques. IM inhibited WT I(HERG) in a concentration-dependent manner with an IC(50) 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 I(HERG) 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 V(1/2) 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 I(HERG). 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. SN - 1347-5215 UR - https://www.unboundmedicine.com/medline/citation/23196655/Blocking_of_the_human_ether_��_go_go_related_gene_channel_by_imatinib_mesylate_ L2 - http://joi.jlc.jst.go.jp/DN/JST.JSTAGE/bpb/b12-00778?lang=en&amp;from=PubMed DB - PRIME DP - Unbound Medicine ER -