Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17).
Serotonin stimulates platelet receptor shedding by tumor necrosis factor-alpha-converting enzyme (ADAM17).
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DOI：
10.1111/j.1538-7836.2009.03476.x
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Wagner DD
中科院分区：
文献类型：
--
作者：
Duerschmied D;Canault M;Lievens D;Brill A;Cifuni SM;Bader M;Wagner DD
外周血清素（5-羟色胺，5-HT）由血小板转运并在刺激时释放。在血小板细胞质中，5-HT被转酰胺为小GTP酶，促进α颗粒释放和初级止血。我们推测5-HT与血小板膜5-HT受体（5-HT 2AR）结合后也能刺激血小板受体脱落。使用Western印迹和流式细胞术测定野生型小鼠、缺乏外周5-HT的Tph 1 −/−小鼠和缺乏功能性肿瘤坏死因子-α-转换酶（TACE，ADAM 17）的小鼠血浆和血清中血小板上粘附受体糖蛋白（GP）Ibα或其脱落片段glycocalicin水平。用流动室实验和活体显微镜观察5-HT_2AR刺激后血小板的粘附特性。Tph 1 −/−血浆和血清中的糖杯素显著减少。在离体血小板中，5-HT诱导GPIbα脱落，当5-HT摄取被选择性5-羟色胺再摄取抑制剂氟西汀抑制时，GPIbα的脱落增加到60%。特异性5-HT 2AR激动和拮抗作用表明该受体活化。TACE不能诱导ΔZn/ΔZn血小板脱落，提示活化的TACE介导GPIbα的脱落。细胞内信号转导涉及p38丝裂原活化蛋白激酶的磷酸化，而不是G蛋白信号转导。5-HT 2AR刺激降低了动脉剪切力（1500 s-1）下血小板与胶原结合的血管性血友病因子的粘附，并降低了肠系膜小动脉中FeCl 3诱导的血栓的掺入。血小板上5-HT 2AR的刺激诱导高剪切条件下关键粘附分子GPIbα的TACE介导的脱落。我们的观察结果表明，通过5-HT可以调节心血管疾病的新途径。
Peripheral serotonin (5-hydroxytryptamine, 5-HT) is transported by platelets and released upon stimulation. In the platelet cytoplasm, 5-HT is transamidated to small GTPases, promoting α-granule release and primary hemostasis. We hypothesized that 5-HT could also stimulate platelet receptor shedding after binding to the membrane 5-HT receptor (5-HT2AR). Western blot and flow cytometry were used to determine levels of the adhesion receptor glycoprotein (GP)Ibα 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 the adhesive properties of platelets after stimulation of 5-HT2AR. Glycocalicin was significantly reduced in Tph1−/− plasma and serum. In isolated platelets, 5-HT induced 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 mediated the shedding of 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−1) and incorporation into FeCl3-induced thrombi in mesenteric arterioles. Stimulation of 5-HT2AR on platelets induces TACE-mediated shedding of GPIbα, the key adhesion molecule under high shear conditions. Our observations demonstrate a new pathway through which 5-HT could modulate cardiovascular disease.
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DOI：
10.1196/annals.1432.042
发表时间：
2008-01-01
期刊：
DRUG ADDICTION: RESEARCH FRONTIERS AND TREATMENT ADVANCES
影响因子：
--
作者：
Rothman, Richard B.;Zolkowska, Dorota;Baumann, Michael H.
通讯作者：
Baumann, Michael H.
影响因子：
56.9
作者：
COHEN, RA;SHEPHERD, JT;VANHOUTTE, PM
通讯作者：
VANHOUTTE, PM
影响因子：
20.1
作者：
Bergmeier, W;Piffath, CL;Wagner, DD
通讯作者：
Wagner, DD
影响因子：
37.8
作者：
Dempsie, Yvonne;Morecroft, Ian;MacLean, Margaret R.
通讯作者：
MacLean, Margaret R.
影响因子：
20.3
作者：
Kanaji, T;Russell, S;Ware, J
通讯作者：
Ware, J