Details

Autor(en) / Beteiligte

• Sah, Renu
• Galeffi, Francesca
• Ahrens, Rebecca
• Jordan, Gwendolyn
• Schwartz‐Bloom, Rochelle D.

Titel

Modulation of the GABAA‐gated chloride channel 
by reactive oxygen species

Ist Teil von

• Journal of neurochemistry, 2002-02, Vol.80 (3), p.383-391

Ort / Verlag

Oxford, UK: Blackwell Science, Ltd

Erscheinungsjahr

2002

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The accumulation of reactive oxygen species during cellular injury leads to oxidative stress. This can have profound effects on ionic homeostasis and neuronal transmission. γ‐Aminobutyric acid (GABA) neurotransmission is sensitive to reactive oxygen species, but most studies have indicated that this is due to alterations in GABA release. Here, we determined whether reactive oxygen species can alter GABAA receptor‐gated Cl– channels in the adult hippocampus. First, we measured the effects of hydrogen peroxide on intracellular Cl– using UV laser scanning confocal microscopy and the Cl–‐sensitive probe, 6‐methoxy‐N‐ethylquinolium iodide (MEQ). Superfusion of adult rat hippocampal slices with hydrogen peroxide for 10 min decreased MEQ fluorescence (elevation in [Cl–]i) significantly in area CA1 pyramidal cell soma. Alterations in [Cl–]i were prevented by the vitamin E analog Trolox, an antioxidant that scavenges free radicals. After exposure of slices to hydrogen peroxide, the ability of the GABA agonist muscimol to increase [Cl–]i was attenuated. To determine if GABAA receptors were sensitive to oxidative insults, the effect of hydrogen peroxide on the binding of [35S]t‐butylbicyclophosphorothionate (TBPS) to GABA‐gated Cl– channels was measured using receptor autoradiography and homogenate binding assays. Hydrogen peroxide inhibited [35S]TBPS binding in a regionally selective manner, with the greatest inhibition in cerebral cortex, hippocampus and striatum, areas␣vulnerable to oxidative stress. Similarly, xanthine and xanthine oxidase, which generate superoxide radicals, reduced [35S]TBPS binding in these regions. The effect of hydrogen peroxide on [35S]TBPS binding was non‐competitive and was prevented by Trolox and the iron chelator, deferoxamine. We conclude that reactive oxygen species may compromise GABAA‐mediated neuronal inhibition via interaction with pre and postsynaptic sites. A reduction in GABAA‐gated Cl– channel function during periods of oxidative stress may contribute to the development of neuronal damage.