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

eLife (2018-09-28)
Kira M Düsterwald, Christopher B Currin, Richard J Burman, Colin J Akerman, Alan R Kay, Joseph V Raimondo
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.

MATERIALS
Product Number
Brand
Product Description

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Canrenoic acid potassium salt, powder
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Gey′s Balanced Salt Solution, liquid, sterile-filtered, suitable for cell culture
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