Membrane receptors, involved in up-regulation of calcium channels in bovine adrenal chromaffin cells, chronically exposed to ethanol.
Release of catecholamines, induced by carbachol, from bovine adrenal chromaffin cells, maintained in culture, is potently inhibited by the presence of ethanol (50 mM). This inhibition is prevented by the concomitant presence of bicuculline (1 microM) or by the inverse agonist at the benzodiazepine receptor, Ro 15 4513 (50 nM), arguing that the effect of ethanol is, at least, partly due to potentiation of endogenous GABA at the GABAA receptor sites on these cells. Exposing cells to medium containing ethanol (200 mM) for 4 days results in an approximately 100% increase in binding sites for [3H]dihydropyridine on membranes of adrenal chromaffin cells. This increase in binding sites was largely prevented by the presence in the culture medium of Ro 15 4513 (50 nM), the dihydropyridine calcium channel agonist BAY K 8644 (50 nM) or the calcium channel antagonist, nitrendipine (50 nM). The results strongly suggest that the increase in binding sites for [3H]dihydropyridine represents an adaptation of cells to overcome the inhibitory effect of ethanol on the excitability of cells (which is, at least partly, due to some action at the GABAA receptor). The protein containing the receptor site for dihydropyridine drugs is clearly also involved in controlling its up-regulation by ethanol, but this is probably not directly related to its channel function, since both activators and inhibitors of the dihydropyridine-sensitive channel prevented ethanol-induced up-regulation of binding sites for [3H]dihydropyridine.
Brennan
C H
CH
Department of Pharmacology, King's College Strand, London, U.K.
Lewis
A
A
Littleton
J M
JM
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D000431:Ethanol / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D001386:Azides; D015220:Calcium Channels; D002395:Catecholamines; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D001569:Benzodiazepines; D000431:Ethanol; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002217:Carbachol; C042957:Ro 15-4513; D009568:Nitrendipine; D001640:Bicuculline