Inhibition of mechanistic target of rapamycin signaling decreases levels of O-GlcNAc transferase and increases serotonin release in the human placenta
| Autor: | Theresa L. Powell, Thomas Jansson, Anita Kramer, Amy C. Kelly, Fredrick J. Rosario |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Blood Platelets
0301 basic medicine Serotonin medicine.medical_specialty Placenta mTORC1 Mechanistic Target of Rapamycin Complex 1 N-Acetylglucosaminyltransferases mTORC2 Article Umbilical vein Serotonin secretion Umbilical Cord 03 medical and health sciences Fetus 0302 clinical medicine Pregnancy Internal medicine medicine Humans Monoamine Oxidase Mechanistic target of rapamycin Cells Cultured PI3K/AKT/mTOR pathway biology Chemistry TOR Serine-Threonine Kinases Trophoblast General Medicine Trophoblasts 030104 developmental biology medicine.anatomical_structure Endocrinology biology.protein Female 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Clin Sci (Lond) |
| ISSN: | 1470-8736 0143-5221 |
| DOI: | 10.1042/cs20201050 |
| Popis: | Changes in placental function, in particular down-regulation of placental O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) in response to maternal stress and increased placental secretion of serotonin into the fetal circulation following maternal infection, have been mechanistically linked to adverse neurodevelopment in mice. We hypothesized that mechanistic target of rapamycin (mTOR) signaling is a key regulator of trophoblast serotonin synthesis and OGT protein expression and that serotonin is secreted by the human placenta into the fetal circulation. Placental homogenates (n=46) from elective terminations at 8–22 weeks of gestation and from healthy-term women were sexed and the protein levels of OGT and enzymes involved in serotonin synthesis was determined. Primary human trophoblast (PHT) cells were isolated from normal term placenta (n=27), cultured and transfected (n=8) with siRNA targeting a scramble sequence (control), raptor (inhibits mTOR Complex 1 (mTORC1)), or rictor (inhibits mTOR Complex 2 (mTORC2)). Subsequently, conditioned media and PHT cell lysates were collected. Free serotonin concentration was measured using ELISA in cell culture media and in platelet-depleted normal term umbilical vein and artery plasma (n=38). Both mTORC1 and mTORC2 inhibition down-regulated OGT levels in PHT cells. The level of serotonin synthesis enzyme tryptophan hydroxylase (TPH-1) was higher in early gestation female placentas and at term serotonin concentration was three-fold higher in the umbilical vein than in the umbilical artery. Inhibition of mTORC2, but not mTORC1, increased cultured PHT cell serotonin secretion. Our data are consistent with the model that mTOR signaling is a key regulator of trophoblast serotonin synthesis and OGT protein expression. |
| Databáze: | OpenAIRE |
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