Document Detail


Dexamethasone enhances the norepinephrine-induced ERK/MAPK intracellular pathway possibly via dysregulation of the alpha2-adrenergic receptor: implications for antidepressant drug mechanism of action.
MedLine Citation:
PMID:  20605057     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Shiri P Yaniv; Anat Lucki; Ehud Klein; Dorit Ben-Shachar
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of cell biology     Volume:  89     ISSN:  1618-1298     ISO Abbreviation:  Eur. J. Cell Biol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-07-20     Completed Date:  2010-11-22     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  7906240     Medline TA:  Eur J Cell Biol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  712-22     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier GmbH. All rights reserved.
Affiliation:
Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel.
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MeSH Terms
Descriptor/Qualifier:
Antidepressive Agents / pharmacology*
Butadienes / pharmacology
Cell Line, Tumor
Cyclic AMP Response Element-Binding Protein / metabolism
Desipramine / pharmacology
Dexamethasone / pharmacology*
Down-Regulation
Drug Synergism
Enzyme Activation
Flavonoids / pharmacology
Glucocorticoids / pharmacology*
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Signaling System / drug effects*
Mitogen-Activated Protein Kinases / antagonists & inhibitors,  metabolism
Neuroblastoma
Nitriles / pharmacology
Norepinephrine / pharmacology*
Proto-Oncogene Proteins c-fos / metabolism
Receptors, Adrenergic, alpha-2 / metabolism*
Transcription Factor AP-1 / genetics,  metabolism
Chemical
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/ADRA2A protein, human; 0/Antidepressive Agents; 0/Butadienes; 0/Cyclic AMP Response Element-Binding Protein; 0/Flavonoids; 0/Glucocorticoids; 0/Nitriles; 0/Proto-Oncogene Proteins c-fos; 0/Receptors, Adrenergic, alpha-2; 0/Transcription Factor AP-1; 0/U 0126; 50-02-2/Dexamethasone; 50-47-5/Desipramine; 51-41-2/Norepinephrine; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases

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