Regulation of platelet phospholipase C

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Abstract
We have investigated factors affecting the activation of phospholipase C in human platelets. Prior exposure of platelets to phorbol esters that stimulate protein kinase C inhibits the activation of phospholipase C in response to a variety of receptor-directed agonists, including x- and y-thrombin and thromboxane A 2 analogues. Such activation has been assayed by measurements of accumulated InsP 3 (including Ins(l,4,5)P 3 and Ins(l,3,4)P 3 ) and PtdOH. Inhibition is not overcome by Ca 2+ ionophores, and substances that block or mimic Na+-H + exchange neither block nor mimic these inhibitory effects. Cyclic AMP and cyclic GMP, other agents known to inhibit phospholipase C activation, do not accumulate in platelets exposed to phorbol esters. Although a portion of the effects of phorbol ester on InsP 3 accumulation may be explained by 5-phosphomonoesterase activity, it is likely that more direct effects on phospholipase C are being exerted as well, and contribute the major inhibitory route. We have examined the susceptibility of adenylyl cyclase-associated G 1 and ‘G p ’- activated phospholipase C to inhibitory ADP-ribosylation by pertussis toxin-derived enzyme (S 1 protomer) administered to saponin-permeabilized platelets. The effects of a-thrombin on adenylyl cyclase can be inhibited by up to 50% by S 1 at which point inhibition of phospholipase C is barely detectable. Thromboxane A 2 analogues, which do not affect adenylyl cyclase (G 1 ), stimulate phospholipase C; this effect is not impaired by Sr We therefore propose that the inhibitory effects of phorbol esters on the activation of phospholipase C are not mediated primarily by effects on G 1 .

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