Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5816179 | Neuropharmacology | 2009 | 10 Pages |
Abstract
Hypoxia modifies GABAA receptor (GABAAR) function and can cause seizures, encephalopathy or myoclonus. To characterize the effects of hypoxia on neuronal GABAARs, we subjected rat cortical neurons to 1% O2 for 2, 4 or 8Â h, followed by recovery times of 0-96Â h, and used whole-cell and perforated patch-clamp recording to assess GABAAR currents and pharmacology. Hypoxic exposure for 4Â h caused downregulation of maximal GABA current immediately following hypoxia and after 48Â h recovery without changing the EC50 for GABA. Two- and eight-hour hypoxic exposures had inconsistent effects on GABAAR currents. Maximal diazepam potentiation was increased immediately following 4Â h hypoxia, while potentiation by zolpidem was increased after 48Â h recovery. Pentobarbital enhancement and zinc inhibition of GABA currents were unchanged. Hypoxia also caused a depolarizing shift in the reversal potential of GABA-induced Clâ currents after 24Â h recovery. The L-type voltage-gated calcium channel (L-VGCC) blocker, nitrendipine, during hypoxia or control treatment prevented the reduction in GABAAR currents, and increased control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation 48Â h after hypoxia, and blocked the depolarizing shift in Clâ reversal potential 24Â h after hypoxia. The effects of hypoxia on maximal GABAAR currents, zolpidem pharmacology and Clâ reversal potential thus require depolarization-induced calcium entry via L-VGCCs, and constitutive L-VGCC activity appears to reduce maximal GABAAR currents in control neurons via a calcium-dependent process. Calcium-dependent modulation of GABAAR currents via L-VGCCs may be a fundamental regulatory mechanism for GABA receptor function.
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Authors
Liping Wang, L. John Jr.,