Neuronal intracellular chloride concentration [Cl-]i is an important determinant of γ-aminobutyric acid type A (GABA A) receptor (GABAAR)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl- across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl -]i. Measurement of [Cl-]i in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A]i) and polyanionic extracellular matrix glycoproteins ([A]o) constrain the local [Cl-]. CCC inhibition had modest effects on [Cl -]i and neuronal volume, but substantial changes were produced by alterations of the balance between [A]i and [A] o. Therefore, CCCs are important elements of Cl- homeostasis, but local impermeant anions determine the homeostatic set point for [Cl-], and hence, neuronal volume and the polarity of local GABAAR signaling.
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