Molecular mechanism of thromboxane A2-induced platelet aggregation -: Essential role for P2TAC and α2A receptors

被引:233
作者
Paul, BZS
Jin, JG
Kunapuli, SP
机构
[1] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19140 USA
[2] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA
[3] Temple Univ, Sch Med, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19140 USA
关键词
D O I
10.1074/jbc.274.41.29108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Thromboxane A, is a positive feedback Lipid mediator produced following platelet activation. The G(q)-coupled thromboxane A(2) receptor subtype, TP alpha, and G(i)-coupled TP beta subtype have been shown in human platelets. ADP-induced platelet aggregation requires concomitant signaling hom two P2 receptor subtypes, P2Y1 and P2T(AC), coupled to G(q) and G(i) respectively. me investigated whether the stable thromboxane A(2) 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 cc-activation of TP alpha and TP beta 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 alpha(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 alpha(2A)-adrenersc receptor. We conclude that whereas thromboxane A(2) causes intracellular calcium mobilization and shape change independently, thromboxane A(2)-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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页码:29108 / 29114
页数:7
相关论文
共 61 条
[1]   INTERACTION OF STABLE PROSTAGLANDIN ENDOPEROXIDE ANALOGS U46619 AND U44069 WITH HUMAN-PLATELET MEMBRANES - COUPLING OF RECEPTORS WITH HIGH-AFFINITY GTPASE AND ADENYLATE-CYCLASE [J].
AVDONIN, PV ;
SVITINAULITINA, IV ;
LEYTIN, VL ;
TKACHUK, VA .
THROMBOSIS RESEARCH, 1985, 40 (01) :101-112
[2]   THE ALPHA-2-ADRENERGIC RECEPTOR ANTAGONIST YOHIMBINE INHIBITS EPINEPHRINE-INDUCED PLATELET-AGGREGATION IN HEALTHY-SUBJECTS [J].
BERLIN, I ;
CRESPOLAUMONNIER, B ;
COURNOT, A ;
LANDAULT, C ;
AUBIN, F ;
LEGRAND, JC ;
PUECH, AJ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1991, 49 (04) :362-369
[3]   AGGREGATION OF BLOOD PLATELETS BY ADENOSINE DIPHOSPHATE AND ITS REVERSAL [J].
BORN, GVR .
NATURE, 1962, 194 (4832) :927-&
[4]  
Boyer JL, 1996, MOL PHARMACOL, V50, P1323
[5]  
BRASS LF, 1988, J BIOL CHEM, V263, P5348
[6]   INOSITOL 1,4,5-TRIPHOSPHATE-INDUCED GRANULE SECRETION IN PLATELETS - EVIDENCE THAT THE ACTIVATION OF PHOSPHOLIPASE-C MEDIATED BY PLATELET THROMBOXANE RECEPTORS INVOLVES A GUANINE-NUCLEOTIDE BINDING PROTEIN-DEPENDENT MECHANISM DISTINCT FROM THAT OF THROMBIN [J].
BRASS, LF ;
SHALLER, CC ;
BELMONTE, EJ .
JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (04) :1269-1275
[7]  
BRESSLER NM, 1979, BLOOD, V53, P167
[8]  
CATTANEO M, 1992, BLOOD, V80, P2787
[9]   Thrombospondin acts via integrin-associated protein to activate the platelet integrin alpha(IIb)beta(3) [J].
Chung, J ;
Gao, AG ;
Frazier, WA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (23) :14740-14746
[10]   INTERRELATIONSHIP OF PROSTAGLANDIN ENDOPEROXIDE-G2 AND CYCLIC NUCLEOTIDES IN PLATELET-FUNCTION [J].
CLAESSON, HE ;
MALMSTEN, C .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1977, 76 (01) :277-284