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Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release.
- Source :
-
Cell [Cell] 2003 Dec 26; Vol. 115 (7), pp. 851-62. - Publication Year :
- 2003
-
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.
- Subjects :
- Animals
Bleeding Time
Blood Coagulation drug effects
Blood Coagulation physiology
Blood Platelets drug effects
Blood Platelets metabolism
Calcium Signaling drug effects
Calcium Signaling physiology
Cell Adhesion drug effects
Cell Adhesion genetics
Cell Aggregation drug effects
Cell Aggregation genetics
Cytoplasm metabolism
Exocytosis drug effects
Exocytosis physiology
Factor VIII metabolism
Humans
Mice
Mice, Knockout
Molecular Sequence Data
Secretory Vesicles drug effects
Secretory Vesicles metabolism
Sequence Homology, Amino Acid
Serotonin metabolism
Serotonin pharmacology
Signal Transduction drug effects
Signal Transduction physiology
Thromboembolism enzymology
Thromboembolism genetics
Transglutaminases metabolism
Tryptophan Hydroxylase genetics
von Willebrand Factor metabolism
Blood Platelets enzymology
GTP Phosphohydrolases metabolism
Secretory Vesicles enzymology
Serotonin deficiency
Tryptophan Hydroxylase deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 0092-8674
- Volume :
- 115
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 14697203
- Full Text :
- https://doi.org/10.1016/s0092-8674(03)01014-6