A selectivity filter at the intracellular end of the acid-sensing ion channel pore

Timothy Lynagh; Emelie Flood; Céline Boiteux; Matthias Wulf; Vitaly V Komnatnyy; Janne M Colding; Toby W Allen; Stephan A Pless

doi:10.7554/eLife.24630

A selectivity filter at the intracellular end of the acid-sensing ion channel pore

Timothy Lynagh, Emelie Flood, Céline Boiteux, Matthias Wulf, Vitaly V Komnatnyy, Janne M Colding, Toby W Allen, Stephan A Pless

24 Citations (Scopus)

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Abstract

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.

Original language	English
Article number	24630
Journal	eLife
Volume	6
Number of pages	21
ISSN	2050-084X
DOIs	https://doi.org/10.7554/eLife.24630
Publication status	Published - 12 May 2017

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10.7554/eLife.24630Licence: CC BY

elife-24630-v2Final published version, 3.29 MBLicence: CC BY

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AU - Lynagh, Timothy

AU - Flood, Emelie

AU - Boiteux, Céline

AU - Wulf, Matthias

AU - Komnatnyy, Vitaly V

AU - Colding, Janne M

AU - Allen, Toby W

AU - Pless, Stephan A

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N2 - 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.

AB - 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.

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JF - eLife

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A selectivity filter at the intracellular end of the acid-sensing ion channel pore

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