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

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.