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Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites.
Upon stimulation with serotonin of washed human platelets prelabeled with [32P]orthophosphate, we found an approximately 250% increase in [32P]phosphatidic acid (PA) formation, a small decrease in [32P]phosphatidylinositol 4,5-bisphosphate, and a concomitant increase in [32P]phosphatidylinositol 4-phosphate. Using [3H]arachidonate for prelabeling, [3H]diacylglycerol accumulated transiently at 10 s after addition of the agonist, [3H]PA increased but to a lower extent compared to 32P-labeled lipid, and the formation of both [3H]polyphosphoinositides increased. The serotonin-induced dose-dependent changes in [32P]PA correlate with its effect on the changes in slope of aggregation of platelets. The potency of 13 drugs to antagonize the serotonin-induced PA formation closely corresponds to both their potency to inhibit platelet aggregation and their binding affinity for serotonin-S2 receptor sites. It is suggested that at least part of the signal transducing system following activation of the serotonin-S2 receptors involves phospholipase C catalyzed inositol lipid breakdown yielding diacylglycerol which is subsequently phosphorylated to PA.
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