Hyperglycemia is one of the leading causes of congenital malformations affecting the neuronal development of embryos. Serotonin (5HT) is a vasoconstrictor compound that also acts as a developmental signal early in rodent embryogenesis. Genetic and pharmacological disruption of 5HT-signaling causes maternal and prenatal morbidity and mortality via mediating high blood pressure and neuroanatomical abnormalities, respectively. Although neurons producing 5HT are among the first to develop in mammalian central nervous system, the biosynthesis of 5HT within the embryo occurs after the serotonergic neurons are first detectable. Before that time, the initial 5HT is derived from the maternal-embryonic circulation by the high-affinity 5HT transport system (SERT) on placenta. SERT on the membranes of the trophoblast cells regulates extracellular 5HT levels and prevents the vasoconstriction in the placental vascular bed and thereby secures a stable blood flow to the embryo. Also, Therefore, SERT plays a major role during the pregnancy for mother and the developing embryo. Our preliminary experiments in rat placenta demonstrated that hyperglycemia associated with diabetes induced mRNA expression of SERT, with no change at protein level. Then, we investigated the effect of sustained hyperglycemia in vitro on the 5HT transport system of HRP-1, rat placenta cells. 5HT uptake rates of cells in the presence of D-glucose at diabetes-like concentrations (30 mmol/l) were decreased significantly as compared to normoglycemic conditions (5.5 mmol/l), and this effect is not cell-type specific, but is sugar-type specific. We next tested the self-association ability of SERT in the presence of diabetic glucose because SERT is an oligomeric protein in the membrane of living cells and that is the preferred conformation. Our preliminary data indicate that at high 30 mM glucose partially diminishes the appearance of oligomeric SERT. The goal of this research project is to identify the underlying mechanism by which high glucose alters the functional expression of SERT. The results of the proposed research will lead to a better understanding of the impact of diabetes on the function and structure of placental SERT, and the impact of placental SERT on the regulation of 5HT levels, which have a central role in neuronal development of embryos. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD053477-02
Application #
7265226
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Grave, Gilman D
Project Start
2006-08-01
Project End
2008-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$68,941
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Biochemistry
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Hadden, Coedy; Fahmi, Tariq; Cooper, Anthonya et al. (2017) Serotonin transporter protects the placental cells against apoptosis in caspase 3-independent pathway. J Cell Physiol 232:3520-3529
Li, Yicong; Hadden, Coedy; Cooper, Anthonya et al. (2016) Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability. Sci Rep 6:22747
Joo, Joung Hyuck; Wang, Bo; Frankel, Elisa et al. (2016) The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. Mol Cell 62:491-506
Li, Yicong; Cooper, Anthonya; Odibo, Imelda N et al. (2016) Discrepancy in Insulin Regulation between Gestational Diabetes Mellitus (GDM) Platelets and Placenta. J Biol Chem 291:9657-65
Basnet, Kristen M; Bentley-Lewis, Rhonda; Wexler, Deborah J et al. (2016) Prevalence of Intervillous Thrombi Is Increased in Placentas from Pregnancies Complicated by Diabetes. Pediatr Dev Pathol 19:502-505
Fraer, Mony; Kilic, Fusun (2015) Serotonin: a different player in hypertension-associated thrombosis. Hypertension 65:942-8
Li, Yicong; Hadden, Coedy; Singh, Preeti et al. (2014) GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proc Natl Acad Sci U S A 111:E5697-705
Ziu, Endrit; Hadden, Coedy; Li, Yicong et al. (2014) Effect of serotonin on platelet function in cocaine exposed blood. Sci Rep 4:5945
Mercado, Charles P; Quintero, Maritza V; Li, Yicong et al. (2013) A serotonin-induced N-glycan switch regulates platelet aggregation. Sci Rep 3:2795
Mercado, Charles P; Byrum, Stephanie; Beggs, Marjorie L et al. (2013) Impact of elevated plasma serotonin on global gene expression of murine megakaryocytes. PLoS One 8:e72580

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