Nongenomic, glucocorticoid receptor-mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons

Neurosci Lett. 2013 Oct 25;554:115-20. doi: 10.1016/j.neulet.2013.08.070. Epub 2013 Sep 8.

Abstract

Depressive disorders have been linked to the combined dysregulation of the hypothalamus-pituitary-adrenal (HPA)-axis and the serotonergic system. The HPA-axis and serotonergic (5-HT) neurons exert reciprocal regulatory actions. It has been reported that glucocorticoid-glucocorticoid receptor (GR) signaling influences serotonin transporter (5-HTT) transcription but data also points to the fact that 5-HTT expression is regulated nongenomically via redistribution of 5-HTT from the cell surface into intracellular compartments. In order to analyze the acute effects of glucocorticoids on 5-HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem (ES) cells derived from the C57BL/6N blastocysts. These postmitotic 5-HT neurons express all relevant serotonergic markers following the application of a growth factor-based differentiation protocol. Increasing concentrations of the GR agonist dexamethasone (Dex) resulted in enhanced, dose-dependent 5-HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation. Inhibition of GR function by the specific GR-antagonist mifepristone abolished the increase in 5-HTT cell surface localization. Hence, our data account for a nongenomic upregulation of 5-HTT cell surface expression by glucocorticoid-GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress. Taken together, we provide a cellular model to analyze and dissect glucocorticoid-5HTT interactions on a molecular level that corresponds to in vivo animal models using C57BL/6N mice.

Keywords: Embryonic stem cells; Glucocorticoid receptor; Nongenomic regulation; Serotonergic neurons; Serotonin transporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Membrane / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Protein Transport
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Serotonergic Neurons / cytology
  • Serotonergic Neurons / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

  • Receptors, Glucocorticoid
  • Serotonin Plasma Membrane Transport Proteins