Abstract
Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv 1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv 1.5 (hKv 1.5) channels. Thirteen single-point mutations were constructed within pore domain of hKv 1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hKv 1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv 1.5 channel. Both desflurane and sevoflurane increased hKv 1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hKv 1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv 1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv 1.5 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. Desflurane and sevoflurane exert an open-channel blocking action on hKv 1.5 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 hKv 1.5 channels by desflurane and sevoflurane.
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