FcγRIIA requires a Gi-dependent pathway for an efficient stimulation of 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 diphosphate (ADP) has been shown to play a major role in platelet activation and aggregation induced by Fc gamma RIIA cross-linking or by sera from HIT patients. 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 clustering-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 significantly affect the tyrosine phosphorylation cascade initiated by Fc gamma RIIA cross-linking. Conversely, the Gi dependent signaling pathway, initiated either by ADP or epinephrine, was required for Fc gamma RIIA-mediated phospholipase C activation and calcium mobilization, Indeed, concomitant signaling from Gi and Fc gamma RIIA itself was necessary for an efficient synthesis of phosphatidylinositol 3,4,5-trisphosphate, a second messenger playing a critical role in the process of phospholipase C gamma2 activation. Altogether, our data demonstrate that converging signaling pathways from Gi and tyrosine kinases are required for platelet secretion and aggregation induced by Fc gamma RIIA. (C) 2000 by The American Society of Hematology.