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Evidence that changes in platelet cyclic AMP levels regulate the fibrinogen receptor on human platelets.

1982; Elsevier BV; Volume: 257; Issue: 24 Linguagem: Inglês

10.1016/s0021-9258(18)33319-2

1083-351X

Stanley E. Gräber, Jacek Hawiger,

Hormonal and reproductive studies

Fibrinogen binds to human platelets after specific receptor sites are exposed by thrombin, ADP, epinephrine, and other stimuli.Since prostaglandin I, (PGI,), a potent activator of platelet adenylate cyclase, prevents mobilization of the fibrinogen receptor by aggregating agents, we investigated the relationship between platelet CAMP levels and fibrinogen receptor status in thrombin-stimulated human platelets.A dose-dependent rise in platelet CAMP in response to two adenylate cyclase agonists, PGIz and forskolin, correlated with progressive inhibition of fibrinogen binding.Moreover, the receptor inhibition produced by either agonist was sustained up to 2 h and was associated with a persistent increase in CAMP levels.The phosphodiesterase inhibitor, l-methyl-3-isobutylxanthine, in the presence of a subthreshold concentration of PGIz also raised CAMP and inhibited fibrinogen binding.In contrast, the effects of PGIz on both CAMP and fibrinogen binding were markedly attenuated by 9-(tetrahydro-2-furyl) adenine, an adenylate cyclase inhibitor.These results indicate that the inhibition of fibrinogen binding by PGIz is linked to its effect on CAMP levels and suggest that elevation of platelet CAMP levels from any cause prevents exposure of the fibrinogen receptor.The membrane receptor for fibrinogen plays an essential role in the aggregation of human platelets.Under normal physiological conditions, this receptor is not readily available on platelets which circulate as single discs in an environment of plasma fibrinogen.However, when platelets become activated by such stimuli as ADP, epinephrine, or thrombin, fibrinogen receptors are exposed (1-3) and fibrinogen, a dimeric molecule with a defined region on each y chain which recognizes specific platelet receptors (4), is then capable of binding to platelets and mediating the formation of platelet aggregates.The biological significance of fibrinogen receptors is further underscored by the behavior of platelets obtained from patients with Glanzmann's thrombasthenia, a congenital deficiency of platelet membrane glycoproteins IIb and IIIa with impaired binding of fibrinogen and absent platelet aggre-