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Neuronal intracellular chloride concentration Cl(-)(i) is an important determinant of γ-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-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 GABA(A)R signaling.
Glykys et al. (2014) studied this question.