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. ? ? ? ?
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