Molecular Mechanism of Thromboxane A2-induced Platelet Aggregation

摘要: Thromboxane A(2) is a positive feedback lipid mediator produced following platelet activation. The G(q)-coupled thromboxane receptor subtype, TPalpha, and G(i)-coupled TPbeta subtype have been shown in human platelets. ADP-induced aggregation requires concomitant signaling from two P2 subtypes, P2Y1 P2T(AC), coupled to G(q) G(i), respectively. We investigated whether the stable mimetic, (15S)-hydroxy-9, 11-epoxymethanoprosta-5Z,13E-dienoic acid (U46619), also causes by through co-activation of TPalpha subtypes. Here we report that secretion blockade with Ro 31-8220, protein kinase C inhibitor, completely inhibited U46619-induced, but not ADP- or thrombin-induced, aggregation. 31-8220 had no effect on U46619-induced intracellular calcium mobilization shape change. Furthermore, change were unaffected A3P5P, receptor-selective antagonist, and/or cyproheptadine, 5-hydroxytryptamine 2A antagonist. Either AR-C66096, P2T(AC) selective abolished inhibition adenylyl cyclase. In addition, AR-C66096 drastically U46619-mediated aggregation, which was further yohimbine, an alpha(2A)-adrenergic relieved activation G(i) pathway either receptor. conclude whereas independently, A(2)-induced cyclase depends exclusively upon other agonists stimulate receptors.