title: Cellular regulation of the benzodiazepine/GABA receptor: arachidonic acid, calcium, and cerebral ischemia.
abstract: The effects of cellular mediators that contribute to ischemia-induced neuronal degeneration on gamma-aminobutyric acid (GABAA)-receptor function were studied. In vitro, phospholipase A2 (PLA2) inhibited muscimol-induced 36Cl- uptake in cerebral cortical synaptoneurosomes. The major hydrolysis product of PLA2 activity, arachidonic acid, also inhibited GABA-mediated 36Cl- uptake. The unsaturated nature of arachidonic acid makes it (and its metabolites) highly susceptible to peroxidation by oxygen radicals. Incubation of synaptoneurosomes with the superoxide radical-generating system, xanthine and xanthine oxidase, decreased muscimol-induced 36Cl- uptake, suggesting that the peroxidation of arachidonic acid and/or its metabolites interferes with GABAA-receptor function. Another factor involved in ischemia-induced neuronal degeneration is an increase in intracellular Ca2+. Calcium also inhibited GABA-mediated 36Cl- flux, consistent with its ability to activate PLA2. In contrast, Mg2+, which blocks Ca2+ channels, enhanced muscimol-induced 36Cl- uptake, consistent with its neuroprotective effects. Each of these cellular processes is activated during cerebral ischemia and can lead to neuronal degeneration. We used a model of transient forebrain ischemia in gerbils to determine if GABAA-receptor regulation is altered in vivo at a time when CA1 hippocampal cells have degenerated. Four days after a 5 minute bilateral carotid artery occlusion, receptor autoradiography was performed to measure the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to the GABA-gated chloride channel. Significant decreases in TBPS binding were observed only in the dendritic layers (stratum oriens and lacunosem moleculare) of the CA1 hippocampus. The results suggest that ischemia-induced cellular processes that contribute to cell death can decrease GABA-gated chloride channels on dendrites of CA1 pyramidal cells, and that GABAA receptors may also reside on neurons afferent to or intrinsic to the dendritic layers of CA1 hippocampus.
authors.affiliation: Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
authors.forename: R D
authors.initials: RD
authors.lastname: Schwartz
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Ehrmann
authors.forename: B E
authors.initials: BE
authors.lastname: Mileson
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology*; D001345:Autoradiography; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000502:physiology*; D003292:Convulsants / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009410:Nerve Degeneration; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology*; D013574:Synaptosomes / Q000502:physiology
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D011963:Receptors, GABA-A; D016718:Arachidonic Acid; C037476:tert-butylbicyclophosphorothionate; D002118:Calcium