Fluvastatin enhances receptor-stimulated intracellular Ca2+ release in human keratinocytes.
We analyzed the effect of isoprenoid depletion by fluvastatin on bradykinin (BK)- and epidermal growth factor (EGF)-mediated Ca2+ mobilization and prostaglandin E2 production, in the human keratinocyte cell line HaCaT. BK and EGF stimulated Ca2+ mobilization in an agonist-dependent manner. The synthesis of prostaglandin E2 paralleled the level of Ca2+ mobilization induced by BK and EGF. Treatment with fluvastatin increased the EGF-promoted but not the BK-promoted Ca2+ mobilization and prostaglandin E2 production in Ca(2+)-containing medium. In the absence of extracellular Ca2+, fluvastatin treatment led to an increase in intracellular Ca2+ release by both agonists. This effect was abolished by depleting the intracellular pool of Ca2+ with thapsigargin. Our findings showed that the intracellular Ca2+ release was dependent on the metabolism of mevalonate and that the Ca2+ mobilization modulated prostaglandin E2 synthesis in human keratinocytes.
Coutant
K D
KD
Department of General Dermatology, Novartis Research Institute, Vienna, Austria. karine.coutant@pharma.novartis.com
Wolff-Winiski
B
B
Ryder
N S
NS
D000814:Aniline Compounds / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects*; D007700:Kinetics; D008798:Mevalonic Acid / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014966:Xanthenes / Q000378:metabolism
D000814:Aniline Compounds; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D014966:Xanthenes; C059715:Fluo-3; D000077340:Fluvastatin; D004815:Epidermal Growth Factor; D019284:Thapsigargin; D015232:Dinoprostone; D008798:Mevalonic Acid; D001920:Bradykinin; D002118:Calcium