title: Post-hypoxic changes in rat cortical neuron GABA A receptor function require L-type voltage-gated calcium channel activation.
abstract: 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% O2 for 2, 4 or 8h, followed by recovery times of 0-96h, and used whole-cell and perforated patch-clamp recording to assess GABA(A)R currents and pharmacology. Hypoxic exposure for 4h caused downregulation of maximal GABA current immediately following hypoxia and after 48h 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 4h hypoxia, while potentiation by zolpidem was increased after 48h 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 24h 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 48h after hypoxia, and blocked the depolarizing shift in Cl(-) reversal potential 24h 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.
authors.affiliation: Department of Neurology, University of Toledo College of Medicine, Health Science Campus, Toledo, OH 43614-2598, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: L John
authors.initials: LJ
authors.lastname: Greenfield
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009568:Nitrendipine / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D009568:Nitrendipine; D015032:Zinc; D010100:Oxygen