Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels

  1. Florian Ullrich
  2. Sandy Blin
  3. Katina Lazarow
  4. Tony Daubitz
  5. Jens Peter von Kries
  6. Thomas J Jentsch  Is a corresponding author
  1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Germany

Abstract

Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated chloride channels had remained unclear. We now used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying anion channel PAORAC/ASOR. ASOR is formed by TMEM206 proteins which display two transmembrane domains (TMs) and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TM2 and at the end of TM1 suggest that these segments line ASOR’s pore. While not belonging to a gene family, TMEM206 has orthologs in probably all vertebrates. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASOR’s role in acid-induced cell death. TMEM206 defines a novel class of ion channels. Its identification will help to understand its physiological roles and the diverse ways by which anion-selective pores can be formed.

Data availability

Raw data are in part presented in the mansucript (e.g. IHC, Western, clamp traces), and as source data files where data points (such as current densities, ratios of permeability etc) have been extracted from original electrophysiological recordings.

Article and author information

Author details

  1. Florian Ullrich

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1153-2040
  2. Sandy Blin

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5762-5149
  3. Katina Lazarow

    Screening Unit, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Tony Daubitz

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Jens Peter von Kries

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Thomas J Jentsch

    Physiology Pathology Ion Transport, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany
    For correspondence
    jentsch@fmp-berlin.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3509-2553

Funding

H2020 European Research Council (Advanced Grant VOLSIGNAL (#740537))

  • Thomas J Jentsch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany

Publication history

  1. Received: June 10, 2019
  2. Accepted: July 17, 2019
  3. Accepted Manuscript published: July 18, 2019 (version 1)
  4. Version of Record published: July 29, 2019 (version 2)

Copyright

© 2019, Ullrich 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. Florian Ullrich
  2. Sandy Blin
  3. Katina Lazarow
  4. Tony Daubitz
  5. Jens Peter von Kries
  6. Thomas J Jentsch
(2019)
Identification of TMEM206 proteins as pore of PAORAC/ASOR acid-sensitive chloride channels
eLife 8:e49187.
https://doi.org/10.7554/eLife.49187
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