title: Local impermeant anions establish the neuronal chloride concentration.
abstract: 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.
authors: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: J
authors: J
authors: Glykys
authors: V
authors: V
authors: Dzhala
authors: K
authors: K
authors: Egawa
authors: T
authors: T
authors: Balena
authors: Y
authors: Y
authors: Saponjian
authors: K V
authors: KV
authors: Kuchibhotla
authors: B J
authors: BJ
authors: Bacskai
authors: K T
authors: KT
authors: Kahle
authors: T
authors: T
authors: Zeuthen
authors: K J
authors: KJ
authors: Staley
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002463:Cell Membrane Permeability; D016764:Cell Polarity; D018118:Chloride Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D011963:Receptors, GABA-A; D011993:Recombinant Fusion Proteins; C415371:clomeleon