Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin αIIbβ3 activation in platelets

Platelet activation is a complex process induced by a variety of stimuli, which act in concert to ensure the rapid formation of a platelet plug at places of vascular injury. We show here that fibrillar collagen, which initiates platelet activation at the damaged vessel wall, activates only a small fraction of platelets in suspension directly, whereas the majority of platelets becomes activated by mediators released from collagen-activated platelets. In Galpha(q)-deficient platelets that do not respond with activation of integrin alpha(IIb)beta(3) to a variety of mediators like thromboxane A(2) (TXA(2)), thrombin, or ADP, collagen at high concentrations was able to induce aggregation, an effect that could be blocked by antagonists of the TXA(2) or P2Y(12) receptors. The activation of TXA(2) or P2Y(12) receptors alone, which in Galpha(q)-deficient platelets couple to G(12)/G(13) and G(i), respectively, did not induce platelet integrin activation or aggregation. However, concomitant activation of both receptors resulted in irreversible integrin alpha(IIb)beta(3)-mediated aggregation of Galpha(q)-deficient platelets. Thus, the activation of G(12)/G(13)- and G(i)-mediated signaling pathways is sufficient to induce integrin alpha(IIb)beta(3) activation. Although G(q)-mediated signaling plays an important role in platelet activation, it is not strictly required for the activation of integrin alpha(IIb)beta(3). This indicates that the efficient induction of platelet aggregation through G-protein-coupled receptors is an integrated response mediated by various converging G-protein-mediated signaling pathways involving G(q) and G(i) as well as G(12)/G(13).