Analysis of the selectivity filter of the voltage-gated sodium channel NavRh

作者:Zhang, Xu; Xia, Mengdie; Li, Yang; Liu, Huihui; Jiang, Xin; Ren, Wenlin; Wu, Jianping; DeCaen, Paul; Yu, Feng; Huang, Sheng; He, Jianhua; Clapham, David E.; Yan, Nieng; Gong, Haipeng*
来源:Cell Research, 2013, 23(3): 409-422.
DOI:10.1038/cr.2012.173

摘要

NaChBac is a bacterial voltage-gated sodium (Na-v) channel that shows sequence similarity to voltage-gated calcium channels. To understand the ion-permeation mechanism of Na-v channels, we combined molecular dynamics simulation, structural biology and electrophysiological approaches to investigate the recently determined structure of NavRh, a marine bacterial NaChBac ortholog. Two Na+ binding sites are identified in the selectivity filter (SF) in our simulations: The extracellular Na+ ion first approaches site 1 constituted by the side groups of Ser181 and Glu183, and then spontaneously arrives at the energetically more favorable site 2 formed by the carbonyl oxygens of Leu179 and Thr178. In contrast, Ca2+ ions are prone to being trapped by Glu183 at site 1, which then blocks the entrance of both Na+ and Ca2+ to the vestibule of the SF. In addition, Na+ permeates through the selective filter in an asymmetrical manner, a feature that resembles that of the mammalian Na-v orthologs. The study reported here provides insights into the mechanism of ion selectivity on Na+ over Ca2+ in mammalian Na-v channels.