Flunitrazepam rapidly reduces GABA(A) receptor subunit protein expression via a protein kinase C-dependent mechanism.
Acute flunitrazepam (1 microM) exposure for 1 h reduced GABA(A) receptor alpha1 (22+/-4%, mean+/-s.e.mean) and beta2/3 (21+/-4%) subunit protein levels in cultured rat cerebellar granule cells. This rapid decrease in subunit proteins was completely prevented by bisindolymaleimide 1 (1 microM), an inhibitor of protein kinase C, but not by N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide (H-89, 4.8 microM), an inhibitor of protein kinases A and G. These results suggest the existence of a benzodiazepine-induced mechanism to rapidly alter GABA(A) receptor protein expression, that appears to be dependent on protein kinase C activity.
Division of Neuroscience, School of Biological Sciences, University of Manchester.
J D
JD
Johnston
S A
SA
Price
D R
DR
Bristow
D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides
D004791:Enzyme Inhibitors; D018757:GABA Modulators; D007211:Indoles; D007546:Isoquinolines; D008301:Maleimides; D011963:Receptors, GABA-A; D013449:Sulfonamides; D005445:Flunitrazepam; D011493:Protein Kinase C; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C088060:bisindolylmaleimide