Significance of cross-talk among ADP, thromboxane A2 and collagen during collagen-induced thrombus formation

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Collagen is the most important platelet activator. It secretes ADP from platelet dense granules and thromboxane A2 (TXA_2) following activation of arachidonic acid cascade. ADP and TXA_2 in turn potentiate the action of collagen. However, detailed mechanism for synergism among collagen, ADP and TXA_2 is not fully elucidated. In this study, we investigated the synergism produced by these activators using bovine and rat platelets. Main findings are as follows.1) U46619, an active analog of TXA_2, did not cause aggregation by itself, but when combined with ADP at a sub threshold concentration, they caused considerable aggregation. Combination of ADP and U46619 synergistically elevated [Ca^<2+>]i. ADP P2Y1 receptor rather than P2Y12 receptor was though to be involved in the increase in [Ca^<2+>]i and aggregation produced 3y combination of ADP and U46619.2) Collagen and ADP also potentiated the aggregation. Activation of integrin a2pi, one of collagen receptor, by ADP may be responsible for the potentiation.3) No synergism was observed between U46619 (TXA_2) and collagen.4) In platelets from cattle or rats with Chediak-Higashi syndrome (CHS), dense granules are poorly developed, thereby ADP secretion was extremely inhibited in these platelets. Decreased secretion of ADP leads to impaired crosstalk between ADP or TXA_2 and that between ADP and collagen, resulting in decreased aggregation response, However, P-selectin release from a-granules was normal in platelets form cattle and rats with CHS.In human platelets it has been reported that ADP synergizes with TXA_2 through P2Y12 receptor, i.e. probably the PI3 kinase - Akt pathway is involved. In contrast, our data suggest that synergism between ADP and TXA_2 is mainly mediated through P2Y1 receptor in bovine platelets. Ca^<2+> may be important for the synergism. Thus, it seems that the mechanism involved in the crosstalk between platelet agonists is different depending on animal species.