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.

Article and author information

Author details

  1. Timothy Lynagh

    Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4888-4098
  2. Emelie Flood

    School of Science, RMIT University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Céline Boiteux

    School of Science, RMIT University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthias Wulf

    Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Vitaly V Komnatnyy

    Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Janne M Colding

    Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Toby W Allen

    School of Science, RMIT University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Stephan A Pless

    Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    stephan.pless@sund.ku.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6654-114X

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.

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

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.

Version history

  1. Received: December 23, 2016
  2. Accepted: May 11, 2017
  3. Accepted Manuscript published: May 12, 2017 (version 1)
  4. Version of Record published: May 30, 2017 (version 2)

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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  1. Timothy Lynagh
  2. Emelie Flood
  3. Céline Boiteux
  4. Matthias Wulf
  5. Vitaly V Komnatnyy
  6. Janne M Colding
  7. Toby W Allen
  8. Stephan A Pless
(2017)
A selectivity filter at the intracellular end of the acid-sensing ion channel pore
eLife 6:e24630.
https://doi.org/10.7554/eLife.24630

Share this article

https://doi.org/10.7554/eLife.24630

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