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

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.