Murray R, FitzGerald G A
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232.
Proc Natl Acad Sci U S A. 1989 Jan;86(1):124-8. doi: 10.1073/pnas.86.1.124.
Thromboxane A2 (TxA2) is a potent platelet agonist that serves as an amplifying signal after exposure of platelets to other stimulants, such as thrombin, in vitro. Exposure of platelets to the TxA2 receptor agonists U46619 and SQ 26,655 (1.4 microM) resulted in a 60-90% decrease in subsequent TxA2 receptor-stimulated aggregation, calcium release, and protein kinase C activation. The desensitization was rapid, with a half-time of 2-3 min. The sequence of events involved in TxA2 receptor desensitization involves initial uncoupling of the receptor from a guanine nucleotide binding (G) protein followed by eventual receptor down-regulation. Consistent with this hypothesis were (i) a 60-70% decrease in SQ 26,655-stimulated platelet GTPase activity, (ii) a shift to the right of the dose-response curve for U46619-stimulated release of calcium [EC50, 275 +/- 51 nM (control)] vs. 475 +/- 71 nM (desensitized); P less than 0.01], and (iii) a delayed loss of receptor sites. In summary, exposure of platelets to TxA2 receptor agonists results in rapid desensitization of the biochemical and functional responses to interaction with its receptor in human platelets. The kinetics of these events are consistent with the hypothesis that this icosanoid functions in the regulation as well as amplification of platelet activation in vivo.
血栓素A2（TxA2）是一种强效的血小板激动剂，在体外血小板暴露于其他刺激物（如凝血酶）后，它作为一种放大信号发挥作用。将血小板暴露于TxA2受体激动剂U46619和SQ 26,655（1.4微摩尔）会导致随后TxA2受体刺激的聚集、钙释放和蛋白激酶C激活减少60 - 90%。脱敏过程迅速，半衰期为2 - 3分钟。TxA2受体脱敏所涉及的事件顺序包括受体最初与鸟嘌呤核苷酸结合（G）蛋白解偶联，随后最终受体下调。与该假设一致的是：（i）SQ 26,655刺激的血小板GTP酶活性降低60 - 70%；（ii）U46619刺激的钙释放剂量 - 反应曲线向右移动[EC50，275±51纳摩尔（对照）对475±71纳摩尔（脱敏）；P<0.01]；以及（iii）受体位点延迟丧失。总之，血小板暴露于TxA2受体激动剂会导致其与人类血小板受体相互作用的生化和功能反应迅速脱敏。这些事件的动力学与该类二十烷酸在体内调节以及放大血小板激活中起作用的假设一致。
