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Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17)

Item Type:Article
Title:Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17)
Creators Name:Duerschmied, D., Canault, M., Lievens, D., Brill, A., Cifuni, S.M., Bader, M. and Wagner, D.D.
Abstract:Background: Peripheral serotonin (5-hydroxytryptamine, 5-HT) is transported by platelets and released upon stimulation. In platelet cytoplasm, 5-HT is transamidated to small GTPases, promoting alpha-granule release and primary hemostasis. Objective: We hypothesized that 5-HT could also stimulate platelet receptor shedding after binding to the membrane 5-HT receptor (5-HT2AR). Methods: Western blot and flow cytometry were used to determine levels of the adhesion receptor GPIbalpha on platelets or its shed fragment glycocalicin in plasma and serum from wild-type mice, Tph1-/- mice lacking peripheral 5-HT, and mice lacking functional tumor necrosis factor-alpha-converting enzyme (TACE, ADAM17). Flow chamber experiments and intravital microscopy were used to examine adhesive properties of platelets after stimulation of 5-HT2AR. Results: Glycocalicin was significantly reduced in Tph1-/- plasma and serum. In isolated platelets, 5-HT induced significant shedding of GPIbalpha, which was increased to 60% when 5-HT uptake was inhibited by the selective serotonin reuptake inhibitor fluoxetine. Specific 5-HT2AR agonism and antagonism suggested activation of this receptor. The shedding could not be induced in TACE(DeltaZn/DeltaZn) platelets, suggesting that activated TACE shed GPIbalpha. Intracellular signaling involved phosphorylation of p38 mitogen-activated protein kinase rather than G protein signaling. 5-HT2AR stimulation decreased platelet adhesion to collagen-bound von Willebrand factor under arterial shear (1,500/s) and incorporation into FeCl(3)-induced thrombi in mesenteric arterioles. Conclusions: Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIbalpha, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5-HT could modulate cardiovascular disease.
Keywords:Platelet, Serotonin, GPIb alpha, TACE, 5-HT2AR, Animals, Mice
Source:Journal of Thrombosis and Haemostasis
Publisher:Blackwell Publishing
Page Range:1163-1171
Date:July 2009
Official Publication:https://doi.org/10.1111/j.1538-7836.2009.03476.x
PubMed:View item in PubMed

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