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

Abstract

AbstractFast 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.