Serotonin is a monoamine whose role in the central nervous system encompasses a e spectrum of physiological and pathological conditions such as sleep, appetite control, aggression, anxiety, depression and schizophrenia. In addition, it participates in the modulation of vascular and endocrine functions. The serotonin transport system, localized in the plasma membrane of only a few specialized cell types, plays an important role in the control of the biological potency of this monoamine and is thus a primary target in the design and development of drugs used in the treatment of serotonin-related disorders. In addition, the serotonin transporter is at least one of the target proteins for the actions of abusable drugs such as cocaine. Despite its therapeutic and pharmacologic relevance, very little is known about the molecular characteristics and regulation of the transporter. The nucleus for the current project is the recent discovery that the human-placental syncytiotrophoblast and a cell line (JAR) of human placental origin express this transporter. The primary goal of the project is to obtain a clear understanding of the molecular and regulatory aspects of this transporter. A major part of the project will be devoted to the investigation of the transporter at the protein level. The long range goals are to understand the expression and regulation of the gene coding for the transporter and to extend these studies to the neuronal serotonin transporter. The proposed study represents a systematic approach to delineate the chemical nature of the polypeptide(s) constituting the transporter. The project is multi-faceted, aiming at purification and characterization of the transporter, functional reconstitution of the purified transporter, and hormonal regulation of the transporter function. These studies will be done using purified human placental brush border membrane vesicles as well as cultured human choriocarcinoma cells. The use of these studies in determining the operational and regulatory mechanisms of the human serotonin transporter in general is just one of the key aspects of the importance of the project. Even more significant is the potential role of serotonin in the placental function. The placenta is vital to the survival of the fetus and until now there has been no indication that serotonin has any role in the placental function. The presence of the serotonin transporter in the brush border (maternal-facing) membrane of the placenta suggests that maternally-- derived serotonin is actively transported into the syncytiotrophoblast in vivo. This opens up a new area for the potential role of serotonin in placental physiology and hence in the growth and development of the human fetus.
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