Open-channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage-gated K_v1.5 channel

Background and Purpose: Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (K_v1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human K_v1.5 (hK_v1.5) channels. Experimental Approach: Thirteen single-point mutations were constructed within pore domain of hK_v1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hK_v1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hK_v1.5 channel. Key Results: Both desflurane and sevoflurane increased hK_v1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hK_v1.5 channels. The inhibitory effect of desflurane or sevoflurane on hK_v1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hK_v1.5 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 hK_v1.5 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 hK_v1.5 channels by desflurane and sevoflurane.