Ceramide selectively inhibits calcium-mediated potentiation of beta-adrenergic-stimulated cyclic nucleotide accumulation in rat pinealocytes.
Interaction between sphingomyelin metabolism and cyclic nucleotide synthesis in rat pinealocytes was investigated by determining the effect of ceramide on adrenergic-stimulated cAMP and cGMP accumulation. Although C2-, C6-, and C8-ceramide had no effect on basal, isoproterenol-, or norepinephrine-stimulated cAMP and cGMP accumulation, they inhibited the potentiation caused by depolarising concentrations of K+ or BayK 8644. Similar inhibition was observed when ceramide metabolism was inhibited by a glucosylceramide synthase inhibitor. In contrast, the potentiation of cAMP and cGMP accumulation caused by other intracellular Ca(2+)-elevating agents such as ionomycin or thapsigargin or by an activator of protein kinase C was not affected by ceramide. Taken together, our results suggest that ceramide selectively inhibits cyclic nucleotide synthesis when the nucleotide synthesis is potentiated by an increase in intracellular Ca2+ through L-type Ca2+ channels and that the sphingomyelin cycle probably plays an important role in the regulation of these channels.
Negishi
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Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Canada.
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D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002518:Ceramides / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006152:Cyclic GMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004357:Drug Synergism; D019833:Genistein / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008614:Meperidine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010870:Pineal Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000701:Analgesics, Opioid; D002518:Ceramides; C026733:4-propionyloxy-4-phenyl-N-methylpiperidine; D010656:Phenylephrine; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D008614:Meperidine; D019833:Genistein; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine