Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A

  1. Andy K M Lam
  2. Raimund Dutzler  Is a corresponding author
  1. University of Zürich, Switzerland

Abstract

TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca2+. This channel contains two independent pores and closely apposed Ca2+ binding sites that are contained within each subunit of a homodimeric protein. Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino C. et. al., 2017). Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations. The currents of constitutively active mutants lose their outward rectification as a function of Ca2+ concentration due to the alleviation of energy barriers for anion conduction. This phenomenon originates from Coulombic interactions between the bound Ca2+ and permeating anions and thus demonstrates that an electrostatic gate imposed by the vacant binding site present in the sterically open pore, is released by Ca2+ binding to enable an otherwise sub-conductive pore to conduct with full capacity.

Data availability

All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Andy K M Lam

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2983-3044
  2. Raimund Dutzler

    Department of Biochemistry, University of Zürich, Zürich, Switzerland
    For correspondence
    dutzler@bioc.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2193-6129

Funding

H2020 European Research Council (ERC no 339116 AnoBest)

  • Raimund Dutzler

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

Publication history

  1. Received: June 14, 2018
  2. Accepted: October 11, 2018
  3. Accepted Manuscript published: October 12, 2018 (version 1)
  4. Version of Record published: October 19, 2018 (version 2)
  5. Version of Record updated: December 7, 2018 (version 3)

Copyright

© 2018, Lam & Dutzler

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. Andy K M Lam
  2. Raimund Dutzler
(2018)
Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A
eLife 7:e39122.
https://doi.org/10.7554/eLife.39122
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