Benzodiazepines enhance the muscimol-dependent activation of phospholipase A2 in glioma C6 cells.
Glioma C6 cells were incubated with [14C]arachidonate to label membrane phospholipids. Muscimol, a selective gamma-aminobutyric acid A receptor agonist, but not (-)-baclofen, a selective gamma-aminobutyric acid B receptor agonist, stimulates [14C]arachidonate release from C6 cells as a result of hydrolysis of a small pool of phosphatidylcholine and phosphatidylethanolamine by phospholipase A2. This release is facilitated by diazepam and a number of other benzodiazepines such as flunitrazepam, medazepam and midazolam (but very little by clonazepam), although these benzodiazepines per se are inactive in causing the release. In addition to increasing the release of [14C]arachidonate, diazepam in the presence of muscimol promotes the release of [14C] prostaglandin D2. Bicuculline inhibits the action of muscimol and facilitation by diazepam. "Peripheral" benzodiazepine ligand, RO 5-4864 (4'-chlordiazepam) antagonizes the action of diazepam, whereas "central" ligand, RO 15-1788, is inactive. The release of arachidonate metabolites stimulated by muscimol and diazepam is unaffected by Cl- channel blockers, picrotoxin and pentylenetetrazol. Based on these results we propose that in glioma C6 cells (and presumably in normal glia) peripheral benzodiazepine receptor interacts functionally with gamma-aminobutyric acid A type of receptor, which appears not to be linked to picrotoxin sensitive Cl- channel, and may be linked to phospholipase A2.
Majewska
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Chuang
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology*; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D015230:Prostaglandin D2; D011457:Prostaglandins D / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D010080:Oxazoles; D011457:Prostaglandins D; D011963:Receptors, GABA-A; D009118:Muscimol; D016718:Arachidonic Acid; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D003975:Diazepam; D015230:Prostaglandin D2