Molecular Determinants for the High-Affinity Blockade of Human Ether-a-go-go-Related Gene K+ Channel by Tolterodine
文献类型：期刊论文
| 作者 | Wang, Na7; Yang, Yang6; Wen, Jing7; Fan, Xin-Rong5; Li, Jian4; Xiong, Bing3 ; Zhang, Jin2; Zeng, Bo7; Shen, Jian-Wu1; Chen, Gui-Lan7
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| 刊名 | JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
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| 出版日期 | 2022-11-01 |
| 卷号 | 80期号:5页码:679-689 |
| ISSN号 | 0160-2446 |
| 关键词 | tolterodine hERG channel molecular docking muscarinic acetylcholine receptor tachycardia overactive bladder |
| DOI | 10.1097/FJC.0000000000001336 |
| 通讯作者 | Shen, Jian-Wu(0907shenjianwu@163.com) ; Chen, Gui-Lan(chenguilan@swmu.edu.cn) |
| 英文摘要 | Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the human ether-a-go-go-related gene (hERG) K+ channel. However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K+ channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine to hERG channel. |
| WOS关键词 | LONG-QT SYNDROME ; VENTRICULAR-TACHYCARDIA ; ANTIMUSCARINIC DRUGS ; ACCURATE DOCKING ; CONCISE GUIDE ; HEART-RATE ; HERG ; MECHANISMS ; PROLONGATION ; TERODILINE |
| 资助项目 | National Natural Science Foundation of China[32171106] ; National Natural Science Foundation of China[81974093] ; CACMS Innovation Fund[CI2021A02206] ; Capital's Funds for Health Improvement and Research[2022-3-4176] ; Joint Research Program of Luzhou City and Southwest Medical University[2020LZXNYDJ21] ; Southwest Medical University[2020ZRQNB046] |
| WOS研究方向 | Cardiovascular System & Cardiology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | LIPPINCOTT WILLIAMS & WILKINS |
| WOS记录号 | WOS:000879544900008 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302903]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shen, Jian-Wu; Chen, Gui-Lan |
| 作者单位 | 1.China Acad Chinese Med Sci, Xiyuan Hosp, Dept Urol, Beijing 100091, Peoples R China 2.Nanchang Univ, Sch Basic Med Sci, Nanchang, Jiangxi, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China 4.Gannan Med Univ, Key Lab Prevent & Treatment Cardiovasc & Cerebrov, Minist Educ, Ganzhou, Peoples R China 5.Affiliated Hosp Southwest Med Univ, Dept Cardiol, Luzhou, Peoples R China 6.Shenzhen Crystalo Biopharmaceut Co Ltd, Shenzhen, Peoples R China 7.Southwest Med Univ, Minist Educ, Key Lab Med Electrophysiol, Luzhou 646000, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Na,Yang, Yang,Wen, Jing,et al. Molecular Determinants for the High-Affinity Blockade of Human Ether-a-go-go-Related Gene K+ Channel by Tolterodine[J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,2022,80(5):679-689. |
| APA | Wang, Na.,Yang, Yang.,Wen, Jing.,Fan, Xin-Rong.,Li, Jian.,...&Chen, Gui-Lan.(2022).Molecular Determinants for the High-Affinity Blockade of Human Ether-a-go-go-Related Gene K+ Channel by Tolterodine.JOURNAL OF CARDIOVASCULAR PHARMACOLOGY,80(5),679-689. |
| MLA | Wang, Na,et al."Molecular Determinants for the High-Affinity Blockade of Human Ether-a-go-go-Related Gene K+ Channel by Tolterodine".JOURNAL OF CARDIOVASCULAR PHARMACOLOGY 80.5(2022):679-689. |
入库方式： OAI收割
来源：上海药物研究所
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