Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method
Nobiletin (NOB) has attracted much attention owing to its outstanding bioactivities. This study aimed to investigate its anti-arrhythmic effect through electrophysiological and molecular docking studies. We assessed the anti-arrhythmic effects of NOB using aconitine-induced ventricular arrhythmia in...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/15175 |
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| author | Youwei Gu Jieru Wang Mengting Li Fei Zhong Jie Xiang Zhengxin Xu |
| author_facet | Youwei Gu Jieru Wang Mengting Li Fei Zhong Jie Xiang Zhengxin Xu |
| author_sort | Youwei Gu |
| collection | DOAJ |
| description | Nobiletin (NOB) has attracted much attention owing to its outstanding bioactivities. This study aimed to investigate its anti-arrhythmic effect through electrophysiological and molecular docking studies. We assessed the anti-arrhythmic effects of NOB using aconitine-induced ventricular arrhythmia in a rat model and the electrophysiological effects of NOB on rat cardiomyocytes utilizing whole-cell patch-clamp techniques. Moreover, we investigated the binding characters of NOB with rNav1.5, rNav1.5/QQQ, and hNa<sub>V</sub>1.5 via docking analysis, comparing them with amiodarone and aconitine. NOB pretreatment delayed susceptibility to ventricular premature and ventricular tachycardia and decreased the incidence of fatal ventricular fibrillation. Whole-cell patch-clamp assays demonstrated that the peak current density of the voltage-gated Na<sup>+</sup> channel current was reversibly reduced by NOB in a concentration-dependent manner. The steady-state activation and recovery curves were shifted in the positive direction along the voltage axis, and the steady-state inactivation curve was shifted in the negative direction along the voltage axis, as shown by gating kinetics. The molecular docking study showed NOB formed a π-π stacking interaction with rNav1.5 and rNav1.5/QQQ upon Phe-1762, which is the homolog to Phe-1760 in hNa<sub>V</sub>1.5 and plays an important role in antiarrhythmic action This study reveals that NOB may act as a class I sodium channel anti-arrhythmia agent. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:44:44Z |
| publishDate | 2022-12-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a0598afb26d14f41a309aabd4961fb942023-11-24T11:14:37ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123231517510.3390/ijms232315175Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking MethodYouwei Gu0Jieru Wang1Mengting Li2Fei Zhong3Jie Xiang4Zhengxin Xu5Department of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaDepartment of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaDepartment of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaDepartment of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaDepartment of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaDepartment of Pharmacology, School of Medicine, Yangzhou University, Yangzhou 225009, ChinaNobiletin (NOB) has attracted much attention owing to its outstanding bioactivities. This study aimed to investigate its anti-arrhythmic effect through electrophysiological and molecular docking studies. We assessed the anti-arrhythmic effects of NOB using aconitine-induced ventricular arrhythmia in a rat model and the electrophysiological effects of NOB on rat cardiomyocytes utilizing whole-cell patch-clamp techniques. Moreover, we investigated the binding characters of NOB with rNav1.5, rNav1.5/QQQ, and hNa<sub>V</sub>1.5 via docking analysis, comparing them with amiodarone and aconitine. NOB pretreatment delayed susceptibility to ventricular premature and ventricular tachycardia and decreased the incidence of fatal ventricular fibrillation. Whole-cell patch-clamp assays demonstrated that the peak current density of the voltage-gated Na<sup>+</sup> channel current was reversibly reduced by NOB in a concentration-dependent manner. The steady-state activation and recovery curves were shifted in the positive direction along the voltage axis, and the steady-state inactivation curve was shifted in the negative direction along the voltage axis, as shown by gating kinetics. The molecular docking study showed NOB formed a π-π stacking interaction with rNav1.5 and rNav1.5/QQQ upon Phe-1762, which is the homolog to Phe-1760 in hNa<sub>V</sub>1.5 and plays an important role in antiarrhythmic action This study reveals that NOB may act as a class I sodium channel anti-arrhythmia agent.https://www.mdpi.com/1422-0067/23/23/15175nobiletinarrhythmiaNa<sub>V</sub>1.5 channelventricular myocytesamiodaroneaconitine |
| spellingShingle | Youwei Gu Jieru Wang Mengting Li Fei Zhong Jie Xiang Zhengxin Xu Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method International Journal of Molecular Sciences nobiletin arrhythmia Na<sub>V</sub>1.5 channel ventricular myocytes amiodarone aconitine |
| title | Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method |
| title_full | Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method |
| title_fullStr | Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method |
| title_full_unstemmed | Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method |
| title_short | Inhibitory Effects of Nobiletin on Voltage-Gated Na<sup>+</sup> Channel in Rat Ventricular Myocytes Based on Electrophysiological Analysis and Molecular Docking Method |
| title_sort | inhibitory effects of nobiletin on voltage gated na sup sup channel in rat ventricular myocytes based on electrophysiological analysis and molecular docking method |
| topic | nobiletin arrhythmia Na<sub>V</sub>1.5 channel ventricular myocytes amiodarone aconitine |
| url | https://www.mdpi.com/1422-0067/23/23/15175 |
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