Cyclic nucleotides control a system which regulates Ca2+ sensitivity of platelet secretion
Cyclic nucleotides control a system which regulates Ca2+ sensitivity of platelet secretion
复制标题
环核苷酸控制调节血小板分泌 Ca2+ 敏感性的系统
作者：
D. Knight;M. Scrutton
细胞对细胞外信号的反应由一种或多种第二信使的细胞内浓度的变化介导1。在血小板中，抑制性激动剂增加细胞内环-3 ′，5 ′-AMP（[环AMP]i（参考文献2，3）），而兴奋性激动剂增加[Ca 2 +]i和/或[1，2-二酰基甘油]i（参考文献4-9），在某些情况下降低[环AMP]i（参考文献10，11）。血小板反应的激活和抑制均归因于[环-3 ′，5 ′-GMP]i的增加（参考文献8，12）。与血小板分泌反应相关的蛋白激酶C的活性被1，2-二酰基甘油和Ca 2+增加（参考文献4、7、8）。环AMP的作用可能涉及抑制Ca 2+向细胞溶质的移动13或刺激细胞内Ca 2+摄取14，以及另外抑制1，2-二酰基甘油形成15，16。环3′，5 ′-GMP（cyclicGMP）与其他第二信使在血小板活化中的关系尚不明确。使用通过暴露于强电场而变得可渗透的血小板17，18，我们在此证明了凝血酶以及12-O-十四酰基佛波醇-13-乙酸酯（TPA）和1-油酰基-2-乙酰基甘油（OAG）对血小板分泌的Ca 2+敏感性的调节，这两种物质都是蛋白激酶C的有效激活剂。凝血酶的作用被环GMP和环AMP选择性地修饰。对OAG和TPA的反应也受到环AMP的调节，但程度要小得多。
Cellular responses to extracellular signals are mediated by changes in the intracellular concentrations of one or more second messengers1. In platelets, inhibitory agonists increase intracellular cyclic-3′,5′-AMP ([cyclic AMP]i (refs 2, 3)) whereas excitatory agonists increase [Ca2+]i and/or [1,2-diacylglycerol]i (refs 4–9), and in some cases decrease [cyclic AMP]i (refs 10,11). Both activation and inhibition of platelet responses have been attributed to an increase in [cyclic-3′,5′-GMP]i (refs 8, 12). The activity of protein kinase C, which is associated with the platelet secretory response, is increased by both 1,2-diacylglycerol and Ca2+ (refs 4, 7, 8). The role of cyclic AMP may involve either inhibition of Ca2+ mobilization to the cytosol13 or stimulation of intracellular Ca2+ uptake14, and in addition inhibition of 1,2-diacylglycerol formation15,16. The relationship between cyclic-3′,5′-GMP (cyclic GMP) and other second messengers in platelet activation has not been defined. Using platelets made permeable by exposure to an intense electric field17,18, we demonstrate here modulation of the Ca2+sensitivity of platelet secretion by thrombin, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) and l-oleyl-2-acetylglycerol (OAG), both potent activators of protein kinase C. The effect of thrombin is selectively modified by cyclic GMP and cyclic AMP. The response to OAG and TPA is also modulated by cyclic AMP but to a much lesser extent.