Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Kira M Düsterwald; Christopher B Currin; Richard J Burman; Colin J Akerman; Alan R Kay; Joseph V Raimondo

doi:10.7554/eLife.39575

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Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Journal article

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Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis

Kira M Düsterwald, Christopher B Currin, Richard J Burman, Colin J Akerman, Alan R Kay and Joseph V Raimondo

eLife, Vol.7, e39575

09/27/2018

DOI: 10.7554/eLife.39575

PMCID: PMC6200395

PMID: 30260315

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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 signaling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

Neuroscience

KCC2

cation-chloride cotransport

NaK-ATPase

Mouse

Rat

synaptic inhibition

Computational and Systems Biology

chloride

impermeant anions

Details

Title: Subtitle: Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis
Creators: Kira M Düsterwald - University of Cape Town
Christopher B Currin - University of Cape Town
Richard J Burman - University of Cape Town
Colin J Akerman - University of Oxford
Alan R Kay - University of Iowa
Joseph V Raimondo - University of Cape Town
Resource Type: Journal article
Publication Details: eLife, Vol.7, e39575
DOI: 10.7554/eLife.39575
PMID: 30260315
PMCID: PMC6200395
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Publisher: eLife Sciences Publications, Ltd
Grant note: ; ERC Grant Agreement 617670 / ; Blue Brain Project / ; DAAD-NRF / ;
Language: English
Date published: 09/27/2018
Academic Unit: Iowa Neuroscience Institute; Biology
Record Identifier: 9983991958502771

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