Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis
- University of Cape Town, South Africa
- University of Oxford, United Kingdom
- University of Iowa, United States
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.
Data availability
Code data is available on GitHub. Experimental data in the form of data spreadsheets has been included, and full experimental data is available on Dryad.
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Data from: Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasisAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Kira Michaela Düsterwald
Christopher Brian Currin
Richard Joseph Burman
Joseph Valentino Raimondo
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.
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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Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis
eLife 7:e39575.
https://doi.org/10.7554/eLife.39575
