https://scholars.lib.ntu.edu.tw/handle/123456789/635472
標題: | Cannabidiol Selectively Binds to the Voltage-Gated Sodium Channel Nav1.4 in Its Slow-Inactivated State and Inhibits Sodium Current | 作者: | Huang, Chiung-Wei Lin, Pi-Chen Chen, Jian-Lin MING-JEN LEE |
關鍵字: | Nav1.4 channel; cannabidiol; fast inactivation; myotonia; slow-inactivation | 公開日期: | 2-九月-2021 | 卷: | 9 | 期: | 9 | 起(迄)頁: | 1141 | 來源出版物: | Biomedicines | 摘要: | Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The binding affinity of CBD to the channel was evaluated using whole-cell recording. The CDOCKER program was employed to model CBD docking onto the Nav1.4 channel to determine its binding sites. Our results revealed no differential inhibition of sodium current by CBD when the channels were in activation or fast inactivation status. However, differential inhibition was observed with a dose-dependent manner after a prolonged period of depolarization, leaving the channel in a slow-inactivated state. Moreover, CBD binds selectively to the slow-inactivated state with a significantly faster binding kinetics (>64,000 M-1 s-1) and a higher affinity (Kd of fast inactivation vs. slow-inactivation: >117.42 μM vs. 51.48 μM), compared to the fast inactivation state. Five proposed CBD binding sites in a bundle crossing region of the Nav1.4 channels pore was identified as Val793, Leu794, Phe797, and Cys759 in domain I/S6, and Ile1279 in domain II/S6. Our findings imply that CBD favorably binds to the Nav1.4 channel in its slow-inactivated state. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/635472 | ISSN: | 2227-9059 | DOI: | 10.3390/biomedicines9091141 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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