ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of G alpha q

Platelets from G alpha q knockout mice are unable to aggregate in response to physiological agonists like adenosine 5'-diphosphate (ADP), thromboxane API thrombin, or collagen, although shape change still occurs in response t o all of these agonists except ADP. ADP-induced platelet aggregation result s from simultaneous activation of the purinergic P2Y(1) receptor coupled to calcium mobilization and shape change and of a distinct P2 receptor, P2cyc , coupled through Gi to adenylyl cyclase inhibition, which is responsible f or completion and amplification of the response, P2cyc could be the molecul ar target of the antithrombotic drug clopidogrel and the adenosine triphosp hate (ATP) analogs AR-C69931MX, AR-C67085, and AR-C66096, The aim of the pr esent study was to determine whether externally added ADP could still act t hrough the Gi pathway in G alpha q-deficient mouse platelets and thereby am plify the residual responses to agonists such as thrombin or collagen. It w as found that (1) ADP and adrenaline still inhibited cyclic AMP accumulatio n in G alpha q-deficient platelets; (2) both agonists restored collagen- bu t not thrombin-induced aggregation in these platelets;(3) the effects of AD P were selectively inhibited in vitro by the ATP analog AR-C69931MX and ex vivo by clopidogrel and hence were apparently mediated by the P2cyc recepto r; and (4) high concentrations of ADP (100 mu mol/L) induced aggregation wi thout shape change in G alpha q-deficient platelets through activation of P 2cyc, Since adrenaline was not able to induce platelet aggregation even at high concentrations, we conclude that the effects of ADP mediated by P2cyc are not restricted to the inhibition of adenylyl cyclase through Gi(2). (Bl ood, 2000;96: 2134-2139) (C) 2000 by The American Society of Hematology.