Phorbol esters modulate thrombin-operated calcium mobilisation and dense granule release in human platelets.
Human alpha-thrombin-induced elevation of cytosolic free calcium ([Ca2+]i) and dense granule release was examined in platelets preincubated with either activators or an inhibitor of protein kinase C. 12-O-Tetradecanoylphorbol 13-acetate (TPA) or two 12-deoxy analogues of TPA, when added alone to platelets, did not elevate [Ca2+]i, as monitored by quin2 fluorescence, though small amounts of dense granule release were detected. Preincubation of the platelets with either TPA or 12-deoxyphorbol 13-phenylacetate, but not the parent, 4-beta-phorbol, produced a dose-dependent inhibition of the elevation of [Ca2+]i and 5-hydroxytryptamine release induced by human alpha-thrombin. Furthermore, this phorbol ester-mediated inhibition of human alpha-thrombin-induced activation could be prevented by H7 (1-[5-isoquinolinesulphonyl]-2-methylpiperazine), the recently described inhibitor of protein kinase C. These results suggest a role for protein kinase C as a modulator of receptor-operated calcium fluxes in human platelets.
Poll
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C
Westwick
J
J
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000097:blood*; D003594:Cytoplasmic Granules / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D010704:Phorbols / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D010704:Phorbols; D012701:Serotonin; D011493:Protein Kinase C; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium