Dexamethasone enhances the norepinephrine-induced ERK/MAPK intracellular pathway possibly via dysregulation of the alpha2-adrenergic receptor: implications for antidepressant drug mechanism of action.

Abstract

Norepinephrine (NE) and glucocorticoids (GCs) have been shown to oppositely affect various aspects of neuronal plasticity. These findings provided the basis for the plasticity hypothesis of major depression, which suggests that the disease-related impairment in neuronal plasticity is associated with long-term increase in GCs and may be reconstituted by antidepressants and monoamines. To investigate the interaction between GCs and NE, the plasticity-relevant ERK/MAPK pathway was studied in SH-SY5Y neuroblastoma cells treated with dexamethasone (DEX), a synthetic GC, NE, or both. NE treatment activated ERK and c-Jun and increased AP-1 transcriptional activity. Although DEX had no effect, co-treatment caused a prolonged and robust activation of the ERK/AP-1 pathway beyond NE-induced activation. Co-treatment also induced hyperactivation of CREB as compared to NE activation while DEX decreased pCREB. Independent alterations of ERK and CREB suggest an upstream point of interaction. Yohimbine, an alpha(2)-adrenergic receptor (AR) antagonist, prevented the hyperactivation of the ERK/AP-1 pathway and CREB induced by co-treatment. Immunofluorescence showed that after 2h of NE treatment, beta-arrestin was co-localized with the alpha(2)-AR at the plasma membrane while following co-treatment beta-arrestin was diffused within the cell, suggesting that DEX delays AR downregulation by altering beta-arrestin translocation. These results show a novel complex interaction by which GCs augment NE-induced intracellular signaling that may be relevant to antidepressant mode of action.

DOI: 10.1016/j.ejcb.2010.05.002

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@article{Yaniv2010DexamethasoneET, title={Dexamethasone enhances the norepinephrine-induced ERK/MAPK intracellular pathway possibly via dysregulation of the alpha2-adrenergic receptor: implications for antidepressant drug mechanism of action.}, author={Shiri Penina Yaniv and Anat Lucki and Ehud M Klein and Dorit Ben-Shachar}, journal={European journal of cell biology}, year={2010}, volume={89 9}, pages={712-22} }