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Serotonylation of small GTPases is a signal transduction pathway that triggers platelet {alpha}-granule release

Item Type:Article
Title:Serotonylation of small GTPases is a signal transduction pathway that triggers platelet {alpha}-granule release
Creators Name:Walther, D.J. and Peter, J.U. and Winter, S. and Hoeltje, M. and Paulmann, N. and Grohmann, M. and Vowinckel, J. and Alamo-Bethencourt, V. and Wilhelm, C.S. and Ahnert-Hilger, G. and Bader, M.
Abstract: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.
Keywords:Amino Acid Sequence Homology, Bleeding Time, Blood Coagulation, Blood Platelets, Calcium Signaling, Cell Adhesion, Cell Aggregation, Cytoplasm, Exocytosis, Factor VIII, GTP Phosphohydrolases, Knockout Mice, Molecular Sequence Data, Secretory Vesicles, Serotonin, Signal Transduction, Thromboembolism, Transglutaminases, Tryptophan Hydroxylase, Von Willebrand Factor, Animals, Mice
Source:Cell
ISSN:0092-8674
Publisher:Cell Press (U.S.A.)
Volume:115
Number:7
Page Range:851-862
Date:1 January 2003
Official Publication:https://doi.org/10.1016/S0092-8674(03)01014-6
PubMed:View item in PubMed

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