Open-channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage-gated Kv1.5 channel

Yutaka Fukushima, Akiko Kojima, Xinya Mi, Wei Guang Ding, Hirotoshi Kitagawa, Hiroshi Matsuura

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background and Purpose: Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv1.5 (hKv1.5) channels. 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 anaesthetics produce both stimulatory and inhibitory actions on hKv1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv1.5 channels 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 channels 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 channels by desflurane and sevoflurane.

Original languageEnglish
Pages (from-to)3811-3827
Number of pages17
JournalBritish Journal of Pharmacology
Volume177
Issue number16
DOIs
Publication statusPublished - Aug 1 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology

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