Inhibition of inositol phospholipids metabolism and calcium mobilization by cyclic AMP-increasing agents and phorbol ester in neutrophils.
Cyclic AMP-increasing agents such as PGE2 and dibutyryl cAMP inhibited the fMLP-induced inositol phospholipids metabolism mainly through the suppression of the conversion of phosphatidylinositol(PI) to phosphatidylinositol 4,5-bisphosphate(PIP2). A part of this inhibition was found to be caused by the inhibitory effect of cAMP on PI kinase using isolated plasma membranes. On the other hand, 12-O-tetradecanoyl phorbol acetate(TPA) mainly inhibited the conversion of phosphatidylinositol 4-phosphate(PIP) to PIP2 without a significant effect on the fMLP-induced breakdown of PIP2, though direct effect of TPA on PI and PIP kinases was not demonstrated in isolated plasma membranes. Concerning Ca2+ mobilization, both cAMP-increasing agents and TPA inhibited the fMLP-induced second phase of Ca2+ elevation, while they did not affect the first phase of Ca2+ rapid increase. However, Ca2+ ionophore ionomycin-induced Ca2+ elevation was only inhibitable by TPA but not PGE2. These results suggest that cAMP inhibits the fMLP-induced Ca2+ influx, while TPA stimulates Ca2+ removal from cytosol.
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000097:blood*; D000242:Cyclic AMP / Q000097:blood*; D015232:Dinoprostone; D004987:Ethers / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000097:blood* / Q000378:metabolism; D011458:Prostaglandins E / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism
D004987:Ethers; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D011458:Prostaglandins E; D015759:Ionomycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D000242:Cyclic AMP; D011494:Protein Kinases; D015232:Dinoprostone; D002118:Calcium