Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release.
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.
Walther
Diego J
DJ
Max-Planck-Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany. dwalther@molgen.mpg.de
Peter
Jens-Uwe
JU
Winter
Sandra
S
Höltje
Markus
M
Paulmann
Nils
N
Grohmann
Maik
M
Vowinckel
Jakob
J
Alamo-Bethencourt
Victor
V
Wilhelm
Claudia S
CS
Ahnert-Hilger
Gudrun
G
Bader
Michael
M
D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002449:Cell Aggregation / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005169:Factor VIII / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D022142:Secretory Vesicles / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012701:Serotonin / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013923:Thromboembolism / Q000201:enzymology / Q000235:genetics; D011503:Transglutaminases / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000172:deficiency* / Q000235:genetics; D014841:von Willebrand Factor / Q000378:metabolism
D014841:von Willebrand Factor; D012701:Serotonin; C078147:F8 protein, human; D005169:Factor VIII; D014365:Tryptophan Hydroxylase; D011503:Transglutaminases; D020558:GTP Phosphohydrolases