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Biochemical and pharmacological characterisation of the serotonin transporter (SERT) in primary trophoblasts of the human placentas

Increasing evidence suggests that serotonin (5HT, 5-hydroxytryptamine), in addition to its neurotransmitter function, participates in the regulation of developmental processes that may have a long-term mental health implications. Serotonin transporter (SERT) is the principal molecule responsible for the removal of 5HT from the extracellular space and represents the prime target of several antidepressant drugs. This transmembrane protein is highly expressed in the brain, but also in several peripheral organs including placenta. It is assumed that placental SERT plays a role in the regulation of uteroplacental blood flow and/or transplacental transport of 5HT, both of which may impact fetal neurodevelopment. The aim of the present study was to investigate the expression levels of SERT as well as biochemical and pharmacological characteristics of 5HT uptake in primary cells isolated from human placental tissue. Trophoblasts obtained from normal term (37th to 42nd gestational week) placentas (TT) displayed saturable, high-affinity uptake of 3H-5HT, with kinetic parameters (Km and Vmax) comparable to that in nervous tissue. Serotonin uptake by TT was highly sensitive to well-known inhibitors of SERT (i.e. citalopram, paroxetine, fluoxetine, fluvoxamine, clomipramine and imipramine) as well as to SERT-targeting drug of abuse 3, 4- methylenedioxymethamphetamine (MDMA). Consistent with the uptake results, we found relatively high levels of SERT mRNA in TT (10-fold higher than in lymphocytes used as positive control). Surprisingly, uptake of 3H-5HT by the first trimester (7th to 9th gestational week) trophoblasts (FTT) as well as by the endothelial cells of the fetoplacental vasculature (HPEC) was remarkably reduced as compared to TT and did not show clear saturation kinetics within the investigated range of 5HT concentrations (up to 6 M). Furthermore, SERT mRNA levels were greatly diminished in both FTT and HPEC as compared to TT (for about 4- and 200-folds, respectively). In conclusion, the results provide a pharmacological profile of SERT in trophoblasts obtained directly from human term placentas and suggest that the expression and activity of this protein in the human placenta undergoes marked changes over the course of pregnancy. Further studies will address a possible involvement of epigenetic mechanisms in the regulation of SERT gene expression in cells of the human placenta.

SERT; human placenta trophoblast; SSRI; MDMA

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