A026 Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17)

• Published in: Archives of cardiovascular diseases 2009, Vol.102, p.S15-S16
• Main Authors: Canault, M, Duerschmied, D, Lievens, D, Brill, A, Cifuni, S.-M, Bader, M, Wagner, D.-D
• Format: Article
• Language: English
• Subjects: Cardiovascular; Internal Medicine
• ISSN: 1875-2136; 1875-2128
• DOI: 10.1016/S1875-2136(09)72159-X

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 α-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 GPIbα 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 GPIbα, 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 TACEδZn/δZn platelets, suggesting that activated TACE shed GPIbα. 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 (1500/s) and incorporation into FeCl3-induced thrombi in mesenteric arterioles. Conclusions Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIbα, the key adhesion molecule under high shear conditions. Our observations provide a new pathway through which 5-HT could modulate cardiovascular disease.