PMID- 33215629
OWN - NLM
STAT- MEDLINE
DCOM- 20210323
LR  - 20220204
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Print)
IS  - 0143-5221 (Linking)
VI  - 134
IP  - 23
DP  - 2020 Dec 11
TI  - Inhibition of mechanistic target of rapamycin signaling decreases levels of 
      O-GlcNAc transferase and increases serotonin release in the human placenta.
PG  - 3123-3136
LID - 10.1042/CS20201050 [doi]
AB  - 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.
CI  - (c) 2020 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Kelly, Amy Catherine
AU  - Kelly AC
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States 
      of America.
FAU - Kramer, Anita
AU  - Kramer A
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States 
      of America.
FAU - Rosario, Fredrick J
AU  - Rosario FJ
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States 
      of America.
FAU - Powell, Theresa L
AU  - Powell TL
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States 
      of America.
AD  - Department of Pediatrics, Section of Neonatology, University of Colorado Anschutz 
      Medical Campus, Aurora, CO 80045, United States of America.
FAU - Jansson, Thomas
AU  - Jansson T
AD  - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, 
      University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States 
      of America.
LA  - eng
GR  - R01 HD068370/HD/NICHD NIH HHS/United States
GR  - T32 HD007186/HD/NICHD NIH HHS/United States
GR  - UL1 TR002535/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 333DO1RDJY (Serotonin)
RN  - EC 1.4.3.4 (Monoamine Oxidase)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
RN  - EC 2.4.1.- (O-GlcNAc transferase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Blood Platelets/metabolism
MH  - Cells, Cultured
MH  - Female
MH  - Fetus/metabolism
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Monoamine Oxidase/metabolism
MH  - N-Acetylglucosaminyltransferases/blood/*metabolism
MH  - Placenta/*metabolism
MH  - Pregnancy
MH  - Serotonin/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Trophoblasts/metabolism
MH  - Umbilical Cord/metabolism
PMC - PMC8807024
MID - NIHMS1772083
OTO - NOTNLM
OT  - Fetal programming
OT  - fetal development
OT  - neurodevelopmental disorders
OT  - pregnancy
OT  - serotonin (5-HT)
OT  - trophoblast
EDAT- 2020/11/21 06:00
MHDA- 2021/03/24 06:00
PMCR- 2022/02/01
CRDT- 2020/11/20 08:39
PHST- 2020/09/01 00:00 [received]
PHST- 2020/11/02 00:00 [revised]
PHST- 2020/11/20 00:00 [accepted]
PHST- 2020/11/21 06:00 [pubmed]
PHST- 2021/03/24 06:00 [medline]
PHST- 2020/11/20 08:39 [entrez]
PHST- 2022/02/01 00:00 [pmc-release]
AID - 227006 [pii]
AID - 10.1042/CS20201050 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2020 Dec 11;134(23):3123-3136. doi: 10.1042/CS20201050.