A selectivity filter at the intracellular end of the acid-sensing ion channel pore
A selectivity filter at the intracellular end of the acid-sensing ion channel pore
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DOI：
10.7554/elife.24630
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发表时间：
2017-05-12
期刊：
影响因子：
7.7
通讯作者：
Pless, Stephan A.
中科院分区：
文献类型：
--
作者：
Lynagh, Timothy;Flood, Emelie;Pless, Stephan A.
神经传递过程中增加的细胞外质子浓度通过酸敏感离子通道 (ASIC) 转化为兴奋性钠流入。 ASIC 中 10 倍的钠/钾选择性长期以来一直被归因于通道孔的中心收缩，但由于这种结构对传统操作的敏感性，缺乏实验验证。在这里，我们通过将非天然氨基酸纳入通道、工程通道化学计量和进行自由能模拟来探索离子选择性的基础。我们观察到中央缢缩处的“气体带”对钠没有偏好。相反，我们在孔的下端发现了一条谷氨酸和天冬氨酸侧链带，可以优先传导钠。
Increased extracellular proton concentrations during neurotransmission are converted to excitatory sodium influx by acid-sensing ion channels (ASICs). 10-fold sodium/potassium selectivity in ASICs has long been attributed to a central constriction in the channel pore, but experimental verification is lacking due to the sensitivity of this structure to conventional manipulations. Here, we explored the basis for ion selectivity by incorporating unnatural amino acids into the channel, engineering channel stoichiometry and performing free energy simulations. We observed no preference for sodium at the "GAS belt" in the central constriction. Instead, we identified a band of glutamate and aspartate side chains at the lower end of the pore that enables preferential sodium conduction.