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Int. J. Mol. Sci. 2016, 17(10), 1648; doi:10.3390/ijms17101648

Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

1
Department of Pharmacology, Harbin Medical University, No. 194 Xuefu Road, Nangang District, Harbin 150081, China
2
Department of Ophthalmology, the Second Affiliated Hospital, Harbin Medical University, No. 148 Baojian Road, Nangang District, Harbin 150081, China
*
Author to whom correspondence should be addressed.
Academic Editor: Sabrina Angelini
Received: 30 July 2016 / Revised: 3 September 2016 / Accepted: 20 September 2016 / Published: 28 September 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency. View Full-Text
Keywords: quinidine; quinine; hERG (human ether-a-go-go-related gene); stereoselectivity; pharmacological rescue quinidine; quinine; hERG (human ether-a-go-go-related gene); stereoselectivity; pharmacological rescue
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Yan, M.; Fan, P.; Shi, Y.; Feng, L.; Wang, J.; Zhan, G.; Li, B. Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect. Int. J. Mol. Sci. 2016, 17, 1648.

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