A selectivity filter at the intracellular end of the acid-sensing ion channel pore
- University of Copenhagen, Denmark
- RMIT University, Australia
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.
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Author details
Funding
Lundbeckfonden (Lundbeck Foundation Fellowship R139-2012-12390)
- Stephan A Pless
Carlsbergfondet (Equipment Grant 2013_01_0439)
- Stephan A Pless
Det Frie Forskningsråd (Postdoctoral Fellowship 4092-00348B)
- Timothy Lynagh
Australian Research Council (Project Grant DP170101732)
- Toby W Allen
Novo Nordisk Foundation (Project Grant)
- Stephan A Pless
National Health and Medical Research Council (Project Grant APP1104259)
- Toby W Allen
National Institutes of Health (Project Grant U01-11567710)
- Toby W Allen
Lundbeckfonden (Postdoctoral Fellowship R171-2014-558)
- Timothy Lynagh
National Cancer Institute (dd7)
- Toby W Allen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with the recommendations by the by the Danish Veterinary and Food Administration and approved under license 2014−15−0201−00031. Surgery was performed on Xenopus laevis frogs anaesthetized in 0.3% tricaine.
Copyright
© 2017, Lynagh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A selectivity filter at the intracellular end of the acid-sensing ion channel pore
eLife 6:e24630.
https://doi.org/10.7554/eLife.24630
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