挥发性麻醉剂地氟醚和七氟醚对人电压门控Kv1.5通道开放的阻断作用
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挥发性麻醉剂地氟烷和七氟烷对人电压门控Kv1.5通道开放的阻断作用
翻译：冯玉蓉 编辑：冯玉蓉 审校：曹莹
背景与目的：挥发性麻醉剂已被证实会对哺乳动物振动相关的电压门控钾通道（Kv1）有不同的调节作用。本研究旨在探讨地氟烷或七氟烷对人Kv1.5（hKv1.5）通道调节作用的分子和细胞机制。
实验方法：利用定点突变技术在hKv1.5通道的孔域内构建13个单点突变。采用全细胞膜片钳技术观察地氟烷和七氟烷对异源表达的野生型和突变型hKv1.5通道的影响。通过计算机模拟预测地氟烷或七氟烷在hKv1.5通道内的对接状态
主要结果：地氟烷和七氟烷在轻度去极化时均增加hKv1.5电流，而在强去极化时则降低hKv1.5电流，表明这两种麻醉剂对hKv1.5通道既有刺激作用又有抑制作用。地氟烷或七氟烷对hKv1.5通道的抑制作用主要是由于对hKv1.5开放的阻断作用。与野生型通道相比，在T480A、V505A和I508A突变型通道中，地氟烷或七氟烷对hKv1.5通道的抑制作用明显减弱。计算对接模拟预测发现，地氟烷或七氟烷存在于通道孔内腔中，并与Thr479、Thr480、Val505和Ile508接触。
结论和意义：地氟烷和七氟烷通过与通道孔内特定氨基酸的功能性相互作用，对hKv1.5通道的开放产生阻断作用。因此，本研究明确了地氟烷和七氟烷介导的hKv1.5通道抑制性调控的新分子基础。
原始文献来源： Fukushima Y, Kojima A, Mi X, et al. Open-channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage-gated Kv1.5 channel[J]. Br. J. Pharmacol. 2020 May 20.
Open-channel blocking action of volatile anesthetics desflurane and sevoflurane on human voltage-gated Kv1.5 channel
Abstract
Background and Purpose: Volatile anesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv1) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on the human Kv1.5 (hKv1.5) channel.
Experimental Approach: Thirteen single-point mutations were constructed within pore domain of hKv1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hKv1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv1.5 channel.
Key Results: Both desflurane and sevoflurane increased hKv1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anesthetics produce both stimulatory and inhibitory actions on hKv1.5 channel. The inhibitory effect of desflurane or sevoflurane on hKv1.5 channel arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv1.5 channel was significantly attenuated in T480A, V505A and I508A mutant channels, compared with wild-type channel. Computational docking simulation predicted that desflurane or sevoflurane resides within the inner cavity of channel pore and has contact with Thr479, Thr480, Val505 and Ile508.
Conclusion and Implications: Desflurane and sevoflurane exert an open-channel blocking action on hKv1.5 channel by functionally interacting with specific amino acids located within the channel pore. This study thus identifies a novel molecular basis mediating inhibitory modulation of hKv1.5 channel by desflurane and sevoflurane.
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