Phorbol 12-myristate 13-acetate inhibition of leukotriene D4-induced signal transduction was rapidly reversed by staurosporine

• Published in: Biochemical and biophysical research communications Vol. 157; no. 2; pp. 521 - 529
• Main Authors: WINKLER, J. D, SARAU, H. M, FOLEY, J. J, CROOKE, S. T
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier 15.12.1988
• Subjects: Alkaloids - pharmacology; Biological and medical sciences; Calcium - metabolism; Cell physiology; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; Inositol Phosphates - metabolism; Membrane and intracellular transports; Molecular and cellular biology; Phosphatidylinositols - metabolism; Protein Kinase C - antagonists & inhibitors; SRS-A - pharmacology; Staurosporine; Tetradecanoylphorbol Acetate - pharmacology; Time Factors; Tumor Cells, Cultured; Cell culture; Protein kinase C; Enzyme; Induction; Arachidonic acid derivatives; Tumor promotor; HPLC chromatography; Enzyme inhibitor; Leukotriene D4; Inositol phosphate; Calcium Ions; Membrane translocation; Dose activity relation; Signal transduction; Cell line
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(88)80280-8

Activation of leukotriene D4 receptors results in phospholipase C-mediated breakdown of phosphatidylinositol and increases in intracellular Ca2+ in U-937 cells. Treatment (10 min) with phorbol 12-myristate 13-acetate blocked leukotriene D4-induced phosphatidylinositol metabolism and Ca2+ mobilization (IC50 = 0.2 nM). Treatment with 10 nM phorbol 12-myristate 13-acetate produced blockade which was complete within 1 min and no recovery was observed over 7 days. Addition of the protein kinase C inhibitor staurosporine (100 nM) to U-937 cells pretreated with phorbol 12-myristate 13-acetate for 5 min or 24 hr resulted in a rapid reappearance of leukotriene D4-induced Ca2+ mobilization. Half of the response recovered within 2 min, with complete recovery in 20 min. Staurosporine produced a concentration-related recovery of signal transduction, with an EC50 of 30 nM. These data describe cells which have a novel response to phorbol 12-myristate 13-acetate in that the inhibition of leukotriene D4 signal transduction is persistent and yet rapidly reversed by staurosporine.