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Local Impermeant Anions Establish the Neuronal Chloride Concentration

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Science  07 Feb 2014:
Vol. 343, Issue 6171, pp. 670-675
DOI: 10.1126/science.1245423

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Causing Chloride Changes

Because intracellular chloride concentrations largely determine the direction and magnitude of current flow through GABAA channels, the stability of intracellular chloride concentration is important to maintain consistent synaptic inhibition. Glykys et al. (p. 670) examined the mechanisms by which chloride gradients in neurons are established, using chloride imaging with transgenically expressed clomeleon dye. Surprisingly, intracellular chloride was not primarily determined by transporters. Instead, subcellular gradients of immobile anions generated inverse chloride gradients.

Abstract

Neuronal intracellular chloride concentration [Cl]i is an important determinant of γ-aminobutyric acid type A (GABAA) 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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