Glykys, J3; Dzhala, V4; Egawa, K4; Balena, T4; Saponjian, Y4; Kuchibhotla, K V4; Bacskai, B J4; Kahle, K T4; Zeuthen, T2; Staley, K J4
1 Section VIII, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Morphogenesis and Differentiation Program, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.4 unknown
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.
Science (new York, N.y.), 2014, Vol 343, Issue 6171, p. 670-5