Fc gamma RIIA requires a Gi-dependent pathway for an efficient stimulationof phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation

Fc gamma RIIA, the only Fc gamma receptor present in platelets, is involved in heparin-associated thrombocytopenia (HIT), Recently, adenosine diphosph ate (ADP) has been shown to play a major role in platelet activation and ag gregation induced by Fc gamma RIIA cross-linking or by sera from HIT patien ts. Herein, we investigated the mechanism of action of ADP as a cofactor in Fc gamma RIIA-dependent platelet activation, which is classically known to involve tyrosine kinases. We first got pharmacologic evidence that the ADP receptor coupled to Gi was required for HIT sera or Fc gamma RIIA clusteri ng-induced platelet secretion and aggregation. Interestingly, the signaling from this ADP receptor could be replaced by triggering another Gi-coupled receptor, the alpha (2A)-adrenergic receptor. ADP scavengers did not signif icantly affect the tyrosine phosphorylation cascade initiated by Fc gamma R IIA cross-linking. Conversely, the Gi dependent signaling pathway, initiate d either by ADP or epinephrine, was required for Fc gamma RIIA-mediated pho spholipase C activation and calcium mobilization, Indeed, concomitant signa ling from Gi and Fc gamma RIIA itself was necessary for an efficient synthe sis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase C gamma2 activation. Altog ether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induce d by Fc gamma RIIA. (C) 2000 by The American Society of Hematology.