Post-hypoxic changes in rat cortical neuron GABA(A) receptor function require L-type voltage-gated calcium channel activation

作者：Wang Liping; Greenfield L John Jr^*

来源：Neuropharmacology, 2009, 56(1): 198-207.

DOI：10.1016/j.neuropharm.2008.07.004

• Patch-clamp
• Reversal potential
• Gramicidin
• Nitrendipine
• Benzodiazepine
• Zolpidem

Hypoxia modifies GABA(A) receptor (GABA(A)R) function and can cause seizures, encephalopathy or myoclonus. To characterize the effects of hypoxia on neuronal GABA(A)Rs, we subjected rat cortical neurons to 1% O-2 for 2, 4 or 8 h, followed by recovery times of 0-96 h, and used whole-cell and perforated patch-clamp recording to assess GABA(A)R currents and pharmacology. Hypoxic exposure for 4 h caused downregulation of maximal GABA current immediately following hypoxia and after 48 h recovery without changing the EC50 for GABA. Two- and eight-hour hypoxic exposures had inconsistent effects on GABA(A)R currents. Maximal diazepam potentiation was increased immediately following 4 h hypoxia, while potentiation by zolpidem was increased after 48 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 Cl- currents after 24 h recovery. The L-type voltage-gated calcium channel (L-VGCC) blocker, nitrendipine, during hypoxia or control treatment prevented the reduction in GABA(A)R currents, and increased control currents over baseline. Nitrendipine also prevented the increase in zolpidem potentiation 48 h after hypoxia, and blocked the depolarizing shift in Cl- reversal potential 24 h after hypoxia. The effects of hypoxia on maximal GABA(A)R currents, zolpidem pharmacology and Cl- reversal potential thus require depolarization-induced calcium entry via L-VGCCs, and constitutive L-VGCC activity appears to reduce maximal GABA(A)R currents in control neurons via a calcium-dependent process. Calcium-dependent modulation of GABA(A)R currents via L-VGCCs may be a fundamental regulatory mechanism for GABA receptor function.

• 出版日期2009-1