Walther Diego J, Peter Jens-Uwe, Winter Sandra, Höltje Markus, Paulmann Nils, Grohmann Maik, Vowinckel Jakob, Alamo-Bethencourt Victor, Wilhelm Claudia S, Ahnert-Hilger Gudrun, Bader Michael
Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany.
Cell. 2003 Dec 26;115(7):851-62. doi: 10.1016/s0092-8674(03)01014-6.
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.
血清素是中枢神经系统中的一种神经递质。在周围组织中，血清素作为一种广泛存在的激素，参与血管收缩和血小板功能。血清素由两种不同的限速色氨酸羟化酶（TPH）同工酶在外周组织和神经元中独立合成。在此，我们表明，外周TPH和血清素选择性缺乏的小鼠表现出止血功能受损，导致血栓形成和血栓栓塞风险降低，尽管血小板的超微结构未受影响。虽然血清素缺乏的血小板在体外的聚集明显正常，但其在体内的黏附由于黏附性α-颗粒蛋白分泌减弱而降低。在进一步阐明机制时，我们证明，在血小板激活和聚集过程中，血清素被转谷氨酰胺酶转酰胺化为小GTP酶，使这些GTP酶持续激活。我们的数据为一种不依赖受体的信号传导机制提供了证据，本文将其称为“血清素化”，它导致血小板α-颗粒胞吐。
