1 The lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, have been reported to activate platelets. Here we examined e ects of the naturally occurring related sphingosylphosphorylcholine (SPC) on human platelet function. 2 Platelet activation was determined as aggregation, elevation of intracellular Ca 2+ concentrations, surface expression of P-selectin, GP 53, and GP IIb/IIIa neoepitope PAC-1, and of ®brinogen binding to the platelet surface. 3 Platelets were activated by ADP (5 and 20 mM), the thrombin receptor-activating peptide TRAP-6 (5 and 20 mM), the thromboxane A 2 mimetic U-46619 (1 mM) and collagen (20 and 50 mg ml 71 ) but not by SPC (up to 20 mM). 4 SPC concentration-dependently (IC 50 approximately 1 ± 10 mM) inhibited activation of washed human platelets in response to all of the above agonists, with almost complete inhibition occurring at 20 mM SPC. 5 The SPC stereoisomers, D-erythro SPC and L-threo SPC, exhibited similar concentration ± response curves in inhibiting 20 mM ADP-induced platelet aggregation, suggesting that SPC did not act via speci®c lysophospholipid receptors. 6 Although SPC slightly activated platelet protein kinase A (as assessed by VASP phosphorylation), this e ect could not explain the marked platelet inhibition. Possible protein kinase C inhibition also did not explain the inhibition of platelet activation by SPC. On the other hand, SPC suppressed agonist-induced Ca 2+ mobilization and phospholipase C stimulation. 7 These results indicate that the lysophospholipid SPC is an e ective inhibitor of human platelet activation, apparently primarily by uncoupling agonist-activated receptors from their e ectors.
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