FIGURE 8.

PDE3A activation plays a role in cAMP depression in stimulated platelets. Platelets were treated with the indicated compounds/vehicle (0.2% DMSO) for 10 min prior to sequential stimulation with 0.1 μm PGE₁ for 3 min and 0.1 units/ml thrombin or vehicle (control) for 3 min. [cAMP] was measured as described under “Experimental Procedures.” Results are expressed as % of controls (containing all additions except for thrombin) ± S.E. (n = 3, ^*, p > 0.1, ^**, p < 0.05) (A). Proposed model of cAMP regulation in platelets is shown. Elevation of cAMP in response to prostacyclin activates PDE3A via PKA-mediated phosphorylation of Ser³¹². This negative feedback loop limits cAMP accumulation. Upon vascular injury and thrombin stimulation, PAR activation leads to Ca²⁺ release and PKC activation, which promotes dense granule secretion and inhibition of adenylate cyclase by P2Y₁₂ agonism. The concomitant phosphorylation and activation of PDE3A by PKC synergize with G_i signaling to remove cAMP below an inhibitory threshold for platelet activation (B).