Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release
Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release
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DOI：
10.1016/s0092-8674(03)01014-6
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发表时间：
2003-12-26
期刊：
影响因子：
64.5
通讯作者：
Bader, M
中科院分区：
文献类型：
--
作者：
Walther, DJ;Peter, JU;Bader, M
血清素是中枢神经系统中的一种神经递质。在外周，血清素作为一种普遍存在的激素参与血管收缩和血小板功能。血清素在外周组织和神经元中由两种不同的限速色氨酸羟化酶（TPH）同工酶独立合成。在这里，我们发现小鼠选择性外周血TPH和血清素缺乏表现出止血受损，导致血栓形成和血栓栓塞的风险降低，尽管血小板的超微结构不受影响。虽然缺乏血清素的血小板在体外聚集是正常的，但它们在体内的粘附性由于粘附α颗粒蛋白的分泌迟钝而降低。为了进一步阐明其机制，我们证明了在血小板的激活和聚集过程中，血清素被谷氨酰胺转胺酶转化为小的gtpase，使这些gtpase具有组成性活性。我们的数据为受体独立的信号机制提供了证据，这里称为“血清素化”，它导致血小板中α颗粒胞吐。
Serotonin is a neurotransmitter in the central nervous system. In the periphery, serotonin functions as a ubiquitous hormone involved in vasoconstriction and platelet function. Serotonin is synthesized independently in peripheral tissues and neurons by two different rate-limiting tryptophan hydroxylase (TPH) isoenzymes. Here, we show that mice selectively deficient in peripheral TPH and serotonin exhibit impaired hemostasis, resulting in a reduced risk of thrombosis and thromboembolism, although the ultrastructure of the platelets is not affected. While the aggregation of serotonin-deficient platelets in vitro is apparently normal, their adhesion in vivo is reduced due to a blunted secretion of adhesive alpha-granular proteins. In elucidating the mechanism further, we demonstrate that serotonin is transamidated to small GTPases by transglutaminases during activation and aggregation of platelets, rendering these GTPases constitutively active. Our data provides evidence for a receptor-independent signaling mechanism, termed herein as "serotonylation," which leads to alpha-granule exocytosis from platelets.