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This study investigated the inhibitory effects of oligoporin A on platelet aggregation and the mechanism of its action on downstream signaling molecules. Oligoporin A was isolated from the fruiting bodies of Oligoporus tephroleucus (Polyporaceae). The anti-platelet activities of oligoporin A were studied using rat platelets. The effects of oligoporin A on intracellular Ca(2+) mobilization, ATP release, production of the cyclic nucleotides cAMP and cGMP, extracellular signal-regulated kinase (ERK) 2 phosphorylation, and fibrinogen binding to active integrin α(II)(b)β(3) were assessed. Oligoporin A, but not oligoporins B and C, inhibited collagen-induced platelet aggregation in a concentration-dependent manner. Interestingly, oligoporin A did not affect ADP- and thrombin-induced platelet aggregations, which act on different types of membrane receptors. Granule secretion analysis demonstrated that oligoporin A significantly and dose-dependently reduced collagen-induced ATP release and intracellular Ca(2+) mobilization. Additionally, oligoporin A induced the dynamic increase in cAMP and cGMP. Increased cGMP production was further confirmed by the simultaneous production of nitric oxide. Pretreatment with oligoporin A significantly blocked collagen-induced ERK2 phosphorylation. Finally, oligoporin A vaguely diminished the binding of fibrinogen to its cognate receptor, integrin α(II)(b)β(3). The results indicate that oligoporin A inhibits only collagen-induced platelet aggregation mediated through the modulation of downstream signaling molecules. Oligoporin A may be beneficial against cardiovascular disease provoked by aberrant platelet activation.