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J Biol Chem, Vol. 274, Issue 41, 29108-29114, October 8, 1999

Molecular Mechanism of Thromboxane A₂-induced Platelet Aggregation
ESSENTIAL ROLE FOR P2T_AC and _2A RECEPTORS

Benjamin Z. S. Paul, Jianguo Jin^§, and Satya P. Kunapuli^§¶

From the Departments of  Pharmacology and ^§ Physiology, and the ^¶ Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Thromboxane A₂ is a positive feedback lipid mediator produced following platelet activation. The G_q-coupled thromboxane A₂ receptor subtype, TP, and G_i-coupled TP subtype have been shown in human platelets. ADP-induced platelet aggregation requires concomitant signaling from two P2 receptor subtypes, P2Y1 and P2T_AC, coupled to G_q and G_i, respectively. We investigated whether the stable thromboxane A₂ mimetic, (15S)-hydroxy-9,11-epoxymethanoprosta-5Z,13E-dienoic acid (U46619), also causes platelet aggregation by concomitant signaling through G_q and G_i, through co-activation of TP and TP receptor subtypes. Here we report that secretion blockade with Ro 31-8220, a protein kinase C inhibitor, completely inhibited U46619-induced, but not ADP- or thrombin-induced, platelet aggregation. Ro 31-8220 had no effect on U46619-induced intracellular calcium mobilization or platelet shape change. Furthermore, U46619-induced intracellular calcium mobilization and shape change were unaffected by A3P5P, a P2Y1 receptor-selective antagonist, and/or cyproheptadine, a 5-hydroxytryptamine subtype 2A receptor antagonist. Either Ro 31-8220 or AR-C66096, a P2T_AC receptor selective antagonist, abolished U46619-induced inhibition of adenylyl cyclase. In addition, AR-C66096 drastically inhibited U46619-mediated platelet aggregation, which was further inhibited by yohimbine, an _2A-adrenergic receptor antagonist. Furthermore, inhibition of U46619-induced platelet aggregation by Ro 31-8220 was relieved by activation of the G_i pathway by selective activation of either the P2T_AC receptor or the _2A-adrenergic receptor. We conclude that whereas thromboxane A₂ causes intracellular calcium mobilization and shape change independently, thromboxane A₂-induced inhibition of adenylyl cyclase and platelet aggregation depends exclusively upon secretion of other agonists that stimulate G_i-coupled receptors.

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