Down-regulation of the serotonin transporter in hyperreactive platelets counteracts the pro-thrombotic effect of serotonin

Ziu, Endrit; Mercado, Charles P.; Li, Yicong; Singh, Preeti; Ahmed, Billow A.; Freyaldenhoven, Samuel; Lensing, Shelly; Ware, Jerry; Kilic, Fusun

doi:10.1016/j.yjmcc.2012.02.004

Cited by 46 publications

(129 citation statements)

References 46 publications

(106 reference statements)

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“…B, platelets were prepared from non-diabetic and GDM-maternal blood. Following an overnight treatment with (0 -100 nM) insulin, plasma membrane expression of SERT was determined by flow cytometry (55). Mean fluorescence intensity of SERT expression in platelets (300,000 platelets/per assay) isolated from non-diabetics was at similar levels but both groups show a significant elevation in insulin treatment.…”

Section: Discussionmentioning

confidence: 99%

Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta

Li¹,

Cooper²,

Odibo

et al. 2016

Journal of Biological Chemistry

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Earlier findings have identified the requirement of insulin signaling on maturation and the translocation of serotonin (5-HT) transporter, SERT to the plasma membrane of the trophoblast in placenta. Because of the defect on insulin receptor (IR) in the trophoblast of the gestational diabetes mellitus (GDM)-associated placenta, SERT is found entrapped in the cytoplasm of the GDM-trophoblast. SERT is encoded by the same gene expressed in trophoblast and platelets. Additionally, alteration in plasma 5-HT levels and the 5-HT uptake rates are associated with the aggregation rates of platelets. Therefore, here, we investigated a novel hypothesis that GDM-associated defects in platelet IR should change their 5-HT uptake rates, and this should be a leading factor for thrombosis in GDM maternal blood. The maternal blood and the placentas were obtained at the time of cesarean section from the GDM and non-diabetic subjects (n ‫؍‬ 6 for each group), and the platelets and trophoblasts were isolated to determine the IR activity, surface level of SERT, and their 5-HT uptake rates.Interestingly, no significant differences were evident in IR tyrosine phosphorylation or the downstream elements, AKT and S6K in platelets and their aggregation rates in both groups. Furthermore, insulin stimulation up-regulated 5-HT uptake rates of GDM-platelets as it does in the control group. However, the phosphorylation of IR and the downstream elements were significantly lower in GDM-trophoblast and showed no response to the insulin stimulation while they showed 4-fold increase to insulin stimulation in control group. Similarly, the 5-HT uptake rates of GDM-trophoblast and the SERT expression on their surface were severalfold lower compared with control subjects. IR is expressed in all tissues, but it is not known if diabetes affects IR in all tissues equally. Here, for the first time, our findings with clinical samples show that in GDM-associated defect on IR is tissue type-dependent. While IR is impaired in GDM-placenta, it is unaffected in GDM-platelet. Gestational diabetes mellitus (GDM)2 is the most common metabolic complication of pregnancy, affecting up to 10 -15% of all pregnancies (1-7), depending on the diagnostic criteria. GDM carries risks to both mother and fetus including the development of obesity, diabetes, and cardiovascular disease in later life. GDM is defined as carbohydrate intolerance due to the impaired insulin signaling with onset or first recognition during pregnancy (1-5). In GDM, the pancreatic ␤ cells fail to produce enough insulin to overcome insulin resistance, which leads to carbohydrate intolerance (5, 6), and a great potential of developing type II diabetes mellitus (1).Recently, it has been shown that the placenta develops insulin resistance in GDM (8 -10), for reasons that are not well understood. The placenta not only transports nutrients to the growing fetus, but importantly, serotonin (5-HT), 5-hydroxytryptamine, is transported across the placenta and is as an essential molecule for embryogenesis (11,12). Stu...

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Section: Discussionmentioning

confidence: 99%

Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta

Li¹,

Cooper²,

Odibo

et al. 2016

Journal of Biological Chemistry

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“…The asterisk represents the results of a twotailed Student t test with P < 0.001 (compared with normal trophoblast uptake rates). (75,76). Mean fluorescence intensity of SERT expression in trophoblast (5 × 10 4 per assay) isolated from normal placentas (red histogram) was higher than in trophoblast from GDM placentas (blue histogram), black histogram represents negative control.…”

Section: Erp44 Enhances Its Coupling With Sert In Gdm At the Intracelmentioning

confidence: 99%

“…After washing, cells were blocked with 0.5% BSA for 1 hr. Then, they were incubated with CK7 (Novus Biological) primary monoclonal Ab for 1 hr and Alexa Fluor 488 goat anti-mouse secondary Ab for an additional 1 hr at RT (75,76).…”

Section: (44)mentioning

confidence: 99%

GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake

Li¹,

Hadden²,

Singh³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Serotonin (5-HT) transporter (SERT) regulates the level of 5-HT in placenta. Initially, we found that in gestational diabetes mellitus (GDM), whereas free plasma 5-HT levels were elevated, the 5-HT uptake rates of trophoblast were significantly down-regulated, due to impairment in the translocation of SERT molecules to the cell surface. We sought to determine the factors mediating the down-regulation of SERT in GDM trophoblast. We previously reported that an endoplasmic reticulum chaperone, ERp44, binds to Cys200 and Cys209 residues of SERT to build a disulfide bond. Following this posttranslational modification, before trafficking to the plasma membrane, SERT must be dissociated from ERp44; and this process is facilitated by insulin signaling and reversed by the insulin receptor blocker AGL2263. However, the GDM-associated defect in insulin signaling hampers the dissociation of ERp44 from SERT. Furthermore, whereas ERp44 constitutively occupies Cys200/ Cys209 residues, one of the SERT glycosylation sites, Asp208 located between the two Cys residues, cannot undergo proper glycosylation, which plays an important role in the uptake efficiency of SERT. Herein, we show that the decrease in 5-HT uptake rates of GDM trophoblast is the consequence of defective insulin signaling, which entraps SERT with ERp44 and impairs its glycosylation. In this regard, restoring the normal expression of SERT on the trophoblast surface may represent a novel approach to alleviating some GDM-associated complications.serotonin | ERp44 | insulin | serotonin transporter | gestational diabetes mellitus

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“…It became widely recognized that 5-HT is an independent risk factor for platelet aggregation and for thrombus formation in animal models (cf., Section 6) and human patients [19,[45][46][47][48][49]. Plasma 5-HT can support platelet aggregation and thrombus growth through 5-HT 2A -dependent or independent signaling pathways.…”

Section: Pathophysiological Consequences Of Abnormal Platelet Serotonmentioning

confidence: 99%

Immuno-Thrombotic Effects of Platelet Serotonin

Mammadova‐Bach¹,

Mauler²,

Braun³

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Platelets transport and store serotonin at a high concentration in dense granules and release it upon activation. Abnormal serotonin concentrations in the blood plasma or increased platelet serotonin release promote the development of thrombosis, sepsis, allergic asthma, myocardial infarction, and stroke. Consequently, experimental data suggest possible benefits of serotonin receptor blockade or inhibition of platelet serotonin uptake in the indicated human diseases. Here, we highlight the current state of basic biological research regarding the role of platelet serotonin in normal and pathophysiological conditions focusing on thrombotic and inflammatory diseases. We also describe the possible clinical applicability of targeting thrombo-immune-modulatory effects of platelet serotonin to treat common health problems.

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Down-regulation of the serotonin transporter in hyperreactive platelets counteracts the pro-thrombotic effect of serotonin

Cited by 46 publications

References 46 publications

Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta

Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta

GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake

Immuno-Thrombotic Effects of Platelet Serotonin

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