1. Computational and Systems Biology
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Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

  1. Kira Michaela Düsterwald
  2. Christopher Brian Currin
  3. Richard Joseph Burman
  4. Colin J Akerman
  5. Alan R Kay
  6. Joseph Valentino Raimondo  Is a corresponding author
  1. University of Cape Town, South Africa
  2. University of Oxford, United Kingdom
  3. University of Iowa, United States
Research Article
  • Cited 4
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Cite this article as: eLife 2018;7:e39575 doi: 10.7554/eLife.39575

Abstract

Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

Article and author information

Author details

  1. Kira Michaela Düsterwald

    Department of Human Biology, University of Cape Town, Cape Town, South Africa
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3217-5326
  2. Christopher Brian Currin

    Department of Human Biology, University of Cape Town, Cape Town, South Africa
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4809-5059
  3. Richard Joseph Burman

    Department of Human Biology, University of Cape Town, Cape Town, South Africa
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3107-7871
  4. Colin J Akerman

    Department of Pharmacology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6844-4984
  5. Alan R Kay

    Department of Biology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2820-6188
  6. Joseph Valentino Raimondo

    Department of Human Biology, University of Cape Town, Cape Town, South Africa
    For correspondence
    joseph.raimondo@uct.ac.za
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8266-3128

Funding

Mandela Rhodes Foundation

  • Kira Michaela Düsterwald
  • Richard Joseph Burman

DAAD-NRF

  • Christopher Brian Currin

Newton Fund

  • Joseph Valentino Raimondo

Blue Brain Project

  • Joseph Valentino Raimondo

H2020 European Research Council (ERC Grant Agreement 617670)

  • Colin J Akerman

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

Ethics

Animal experimentation: No experiments were performed on animals prior to humane killing using cervical dislocation at P7, every effort was made to minimise stress prior to killing. The use of rats in the UK (furosemide experiment) were in accordance with regulations from the United Kingdom Home Office Animals (Scientific Procedures) Act. Use of mice (electroporation experiment) at the University of Cape Town was in accordance with South African national guidelines (South African National Standard: The care and use of animals for scientific purposes, 2008) and was approved by the University of Cape Town Animal Ethics Committee protocol no 014/035.

Reviewing Editor

  1. Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: June 26, 2018
  2. Accepted: September 24, 2018
  3. Accepted Manuscript published: September 27, 2018 (version 1)
  4. Version of Record published: October 24, 2018 (version 2)
  5. Version of Record updated: October 31, 2018 (version 3)

Copyright

© 2018, Düsterwald 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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