title: Astrocyte Na+ channels are required for maintenance of Na+/K(+)-ATPase activity.
abstract: Astrocytes in vitro and in situ have been shown to express voltage-activated ion channels previously thought to be restricted to excitable cells, including voltage-activated Na+, Ca2+, and K+ channels. However, unlike neurons, astrocytes do not generate action potentials, and the functional role of voltage-activated channels in astrocytes has been an enigma. In order to study the function of Na+ channels in glial cells, we carried out ion flux measurements, patch-clamp recordings, and ratiometric imaging of [Na+]i during blockade of Na+ channels on rat spinal cord astrocytes cultured for 7-10 d. Acute blockade of astrocyte Na+ channels by TTX had multiple effects: (1) TTX reduced, in a dose-dependent manner, Na+/K(+)-ATPase activity measured as unidirectional influx of 86Rb+; (2) TTX depolarized astrocyte membrane potential at a rate of approximately 1 mV/min; (3) TTX (100 microM) reduced [Na+]i; and (4) prolonged exposure to micromolar TTX induced astrocyte death. All these effects of TTX could be mimicked by ouabain or strophanthidin, specific blockers of the Na+/K(+)-ATPase. The effects of TTX and ouabain (or strophanthidin) were not additive. These results suggest that TTX-blockable Na+ channels in glial cells serve functions that do not require their participation in action potential electrogenesis; in particular, we propose that glial Na+ channels constitute a "return" pathway for Na+/K(+)-ATPase function, which permits Na+ ions to enter the cells to maintain [Na+]i at concentrations necessary for activity of the Na+/K(+)-ATPase. Since astrocyte Na+/K(+)-ATPase is believed to participate in [K+]o homeostasis in the CNS, the coupling of Na+ flux through voltage-activated Na+ channels to ATPase activity may provide a feedback loop that participates in the regulation of K+ ion levels in the extracellular space.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510.
authors.forename: H
authors.initials: H
authors.lastname: Sontheimer
authors.forename: E
authors.initials: E
authors.lastname: Fernandez-Marques
authors.forename: N
authors.initials: N
authors.lastname: Ullrich
authors.forename: C A
authors.initials: CA
authors.lastname: Pappas
authors.forename: S G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D001254:Astrocytoma; D002460:Cell Line; D002478:Cells, Cultured; D004594:Electrophysiology / Q000379:methods; D005727:Ganglia, Spinal / Q000166:cytology / Q000502:physiology*; D005910:Glioma; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012413:Rubidium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013327:Strophanthidin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D015222:Sodium Channels; D013779:Tetrodotoxin; D010042:Ouabain; D013327:Strophanthidin; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D012413:Rubidium