Distinct Lipid Rafts in Subdomains from Human Placental Apical Syncytiotrophoblast Membranes

Godoy, Valeria; Riquelme, Gloria

doi:10.1007/s00232-008-9125-5

Cited by 21 publications

(25 citation statements)

References 56 publications

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“…Indeed, treatment with nystatin alone, which sequesters lipid rafts similarly to filipin, had no effect on CVB entry and inhibited entry only when used in combination with the cholesterol synthesis inhibitor progesterone. Unlike other cell types, trophoblasts exhibit specialized lipid raft domains at their apical surfaces (90), which may at least partially contribute to the inability of the lipid sequestering agents filipin or nystatin alone to disrupt CVB entry. In addition, transfection of a siRNA targeting caveolin 1, the transmembrane protein component critical for the formation of caveolae (63), had no effect on CVB infection in these cells, suggesting that lipid rafts, but not caveolae, were necessary for CVB entry into BeWo cells.…”

Section: Discussionmentioning

confidence: 99%

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Delorme-Axford

Sadovsky

Coyne

2013

J Virol

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bMaternal-fetal transmission of group B coxsackieviruses (CVB) during pregnancy has been associated with a number of diverse pathological outcomes, including hydrops fetalis, fetal myocarditis, meningoencephalitis, neurodevelopmental delays, congenital skin lesions, miscarriage, and/or stillbirth. Throughout pregnancy, the placenta forms a critical antimicrobial protective barrier at the maternal-fetal interface. Despite the severity of diseases accompanying fetal CVB infections, little is known regarding the strategies used by CVB to gain entry into placental trophoblasts. Here we used both a trophoblast cell line and primary human trophoblasts to demonstrate the mechanism by which CVB gains entry into polarized placental trophoblasts. Our studies revealed that the kinetics of CVB entry into placental trophoblasts are similar to those previously described for polarized intestinal epithelial cells. Likewise, CVB entry into placental trophoblasts requires decay-accelerating factor (DAF) binding and involves relocalization of the virus from the apical surface to intercellular tight junctions. In contrast, we have identified a divergent mechanism for CVB entry into polarized trophoblasts that is clathrin, caveolin-1, and dynamin II independent but requires intact lipid rafts. In addition, we found that members of the Src family of tyrosine kinases were required for CVB entry. Our studies highlight the complexity of viral entry into human placental trophoblasts and may serve as a model for mechanisms used by diverse pathogens to penetrate the placental barrier.

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Section: Discussionmentioning

confidence: 99%

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Delorme-Axford

Sadovsky

Coyne

2013

J Virol

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“…Apical plasma membrane microdomains were isolated from MVM-and LMVMenriched preparations as a separate detergent-resistant fraction by extraction with Triton X-100, as described by Godoy and Riquelme (2008). In brief, aliquots (0.6 mg) of both isolated membrane fractions were homogenized 30 times in a manual glass homogenizer with 1% Triton X-100 in MES-buffered saline (25 mM MES, pH 6.5, and 150 mM NaCl).…”

Section: Introductionmentioning

confidence: 99%

“…The presence of distinct lipid rafts in the apical plasma membrane domain of placental syncytiotrophoblast has been reported (Godoy and Riquelme, 2008), although the presence of nutrient transporters, particularly nucleoside transporters, in these domains has not been established. In this regard, Western blot detection of nucleoside transporter proteins in purified syncytiotrophoblast membranes and analysis of the distribution of hCNT1, hENT1, and hENT2 in different lipid microdomains were performed.…”

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confidence: 99%

“…To determine whether hCNT1, hENT1, and hENT2 are localized to membrane rafts, we isolated a detergent-resistant membrane fraction by sucrose density centrifugation, as described recently (Godoy and Riquelme, 2008). In Western blots of LMVM-containing gradient fractions (Fig.…”

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confidence: 99%

“…Of interest, the heavy apical MVM showed a completely different distribution for both hCNT1 and hENT1 transporter proteins, being found exclusively in nonraft fractions. The heavy MVM and LMVM fractions used in this study correspond to the finger-like projections and the bottom part between the microvilli, respectively (Godoy and Riquelme, 2008), which also show a heterogeneous population of raft domains (Braccia et al, 2003;Godoy and Riquelme, 2008). The expression of particular cytoskeletal proteins in finger-like projection regions of the microvilli (MVM) that has been proposed to be tightly associated with plasma membrane lipidic microdomains could explain the presence of lipid raft markers in nonraft fractions (Godoy and Riquelme, 2008).…”

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confidence: 99%

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Expression and Distribution of Nucleoside Transporter Proteins in the Human Syncytiotrophoblast

Errasti-Murugarren¹,

Díaz²,

Godoy³

et al. 2011

Mol Pharmacol

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The plasma membrane distribution and related biological activity of nucleoside transporter proteins (NTs) were investigated in human syncytiotrophoblast from term placenta using a variety of approaches, including nucleoside uptake measurements into vesicles from selected plasma membrane domains, NT immunohistochemistry, and subcellular localization (basal, heavy, and light apical membranes as well as raft-enriched membranes from the apical domain). In contrast with other epithelia, in this epithelium, we have identified the high-affinity pyrimidine-preferring human concentrative nucleoside transporter (hCNT) 1 as the only hCNT-type protein expressed at both the basal and apical membranes. hCNT1 localization in lipid rafts is also dependent on its subcellular localization in the apical plasma membrane, suggesting a complex cellular and regional expression. Overall, this result favors the view that the placenta is a pyrimidine-preferring nucleoside sink from both maternal and fetal sides, and hCNT1 plays a major role in promoting pyrimidine salvage and placental growth. This finding may be of pharmacological relevance, because hCNT1 is known to interact with anticancer nucleoside-derived drugs and other molecules, such as nicotine and caffeine, for which a great variety of harmful effects on placental and fetal development, including intrauterine growth retardation, have been reported.

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Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies

Zheng

Yang

Dallmann

2022

The Journal of Clinical Pharma

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There is limited information about the transfer of antidepressants and antipsychotics across the human placenta. The objective of the current review was to systematically screen the scientific literature using relevant keywords to collect quantitative data on placental transfer of these drugs in humans and to give an overview of current modeling approaches used in this context. The collected data encompassed clinically measured fetal:maternal (F:M) concentration ratios (ie, the ratio between drug concentrations measured in the umbilical cord and drug concentrations measured in the mother) and transfer data obtained from ex vivo cotyledon perfusion experiments. These data were found for 18 antidepressants and some of their pharmacologically active metabolites, and for 10 antipsychotics and the metabolites thereof. Based on the collected data, similar maternal and fetal exposure could be observed for only a few compounds (eg, norfluoxetine and desvenlafaxine), whereas for most drugs (eg, paroxetine, sertraline, and quetiapine), fetal exposure appeared to be on average lower than maternal exposure. Venlafaxine appeared to be an exception in that the data indicated equivalent or higher concentrations in the umbilical cord than in the mother. Physiologically based pharmacokinetic (PBPK) models were sporadically used to investigate maternal pharmacokinetics of antidepressants or antipsychotics (eg, for sertraline, aripiprazole, and olanzapine), although without explicitly addressing fetal drug exposure. It is recommended that PBPK modeling is applied more frequently to these drugs. Although no substitute for clinical studies, these tools can help to better understand pregnancy‐induced pharmacokinetic changes and ultimately contribute to a more evidence‐based pharmacotherapy of depression and psychosis in pregnant subjects.

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Distinct Lipid Rafts in Subdomains from Human Placental Apical Syncytiotrophoblast Membranes

Cited by 21 publications

References 56 publications

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Expression and Distribution of Nucleoside Transporter Proteins in the Human Syncytiotrophoblast

Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies

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