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Cited by 475Platelet Disorders and TreatmentsBlood Coagulation and Thrombosis MechanismsProtein Kinase Regulation and GTPase Signaling

Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release

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Walther, Diego J, Peter, Jens-Uwe, Winter, Sandra, Höltje, Markus, Paulmann, Nils, Grohmann, Maik, Vowinckel, Jakob, Alamo-Bethencourt, Victor +3 more·2003·Cell
DOI 10.1016/s0092-8674(03)01014-6
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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.

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  • Transglutamination of the Gln63 residue abolishes the intrinsic and GAP-stimulated GTPase activity of RhoA, leading to its permanent activation.

    “Finally, various types of transglutamination of the Gln63 residue have been found to abolish the intrinsic and GAP-stimulated GTPase activity of RhoA, leading to its permanent activation [74,75,76].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [76]

    The Abstract says transamidation blocks intrinsic GTP-hydrolyzing activity and renders small GTPases constitutively active. The Results show that transamidated RhoA binds an effector strongly even when GDP-bound. Our copy does not establish that the modified residue is Gln63 or that GAP-stimulated GTPase activity is abolished. (LLM, conf=0.85)

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Research works printed but not linked: 22

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Authors
Walther, D. J., Peter, J.-U., Winter, S., Höltje, M., Paulmann, N., Grohmann, M., Vowinckel, J., Alamo-Bethencourt, V., Wilhelm, C. S., Ahnert-Hilger, G., & Bader, M.
Affiliations
  • Max Planck Institute for Molecular Genetics (DE)
  • Max Planck Society (DE)
  • Humboldt-Universität zu Berlin (DE)
  • Max Delbrück Center (DE)
Corresponding author
Walther, Diego J
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2003-12
Volume
115
Issue
7
Pages
851-862
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/s0092-8674(03)01014-6
OpenAlex
W1968415875
Cited by
475
References
0
Citations by year
2026: 17 · 2025: 16 · 2024: 16 · 2023: 21 · 2022: 24 · 2021: 34 · 2020: 35 · 2019: 18 · 2018: 20 · 2017: 26 · 2016: 20 · 2015: 18 · 2014: 14 · 2013: 19 · 2012: 29
FWCI
5.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
serotonin, serotonylation, small GTPases, transglutaminase, tryptophan hydroxylase, platelet adhesion, platelet aggregation, hemostasis, thrombosis, thromboembolism, receptor-independent signaling, exocytosis
MeSH terms
Animals, Bleeding Time, Blood Coagulation, Blood Platelets, Cell Adhesion, Cell Aggregation, Cytoplasm, Exocytosis, Factor VIII, Humans, Molecular Sequence Data, Transglutaminases, Serotonin, Thromboembolism, Tryptophan Hydroxylase, von Willebrand Factor, Signal Transduction, Sequence Homology, Amino Acid, Mice, Knockout, Calcium Signaling, GTP Phosphohydrolases, Secretory Vesicles, Mice

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