The intracellular signaling pathways by which G protein–coupled receptors on the platelet surface initiate aggregation, a critical process for hemostasis and thrombosis, are not well understood. In particular, the contribution of the Gi pathway has not been directly addressed. We have investigated the activation of platelets from mice in which the gene for the predominant platelet Gαi subtype, Gαi2, has been disrupted. In intact platelets from Gαi2-deficient mice, the inhibition of adenylyl cyclase by ADP was found to be partially impaired compared with wild-type platelets. Moreover, both ADP-dependent platelet aggregation and the activation of the integrin αIIbβ3 (GPIIb-IIIa) were strongly reduced in platelets from Gαi2-deficient mice. In addition, Gαi2-deficient platelets displayed impaired activation at low thrombin concentrations. This defect was mimicked by blocking the adenylyl cyclase–coupled platelet ADP receptor (P2Y12) on wild-type platelets with a selective antagonist. These observations suggest that Gαi2 is involved in the inhibition of platelet adenylyl cyclase in vivo and is a critical component of the signaling pathway for integrin activation by ADP, resulting in platelet aggregation. In addition, thrombin-dependent activation of mouse platelets is mediated, at least in part, by secreted ADP acting on the Gαi2–linked ADP receptor.
Hans-Michael Jantzen, David S. Milstone, Laurent Gousset, Pamela B. Conley, Richard M. Mortensen
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