Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation

Abstract

ADP is an important platelet agonist causing shape change and aggregation required for physiological hemostasis. We recently demonstrated the existence of two distinct G protein-coupled ADP receptors on platelets, one coupled to phospholipase C, P2Y1, and the other to inhibition of adenylyl cyclase, P2T AC . In this study, using specific antagonists for these two receptors, we demonstrated that concomitant intracellular signaling from both the P2T AC and P2Y1 receptors is essential for ADP-induced platelet aggregation. Inhibition of signaling through either receptor, by specific antagonists, is sufficient to block ADP-induced platelet aggregation. Furthermore, signaling through the P2T AC receptor could be replaced by activation of α 2A -adrenergic receptors. On the other hand, activation of serotonin receptors supplements signaling through the P2Y1 receptor. Moreover, this mechanism of ADP-induced platelet aggregation could be mimicked by coactivation of two non-ADP receptors coupled to G i and G q , neither of which can cause platelet aggregation by itself. We propose that platelet aggregation results from concomitant signaling from both the G i and G q , a mechanism by which G protein-coupled receptors elicit a physiological response.