title: Dexamethasone in the presence of desipramine enhances MAPK/ERK1/2 signaling possibly via its interference with β-arrestin.
abstract: Antidepressant medication is the standard treatment for major depression disorder (MDD). However, the response to these treatments is often incomplete and many patients remain refractory. In the present study, we show that the glucocorticoid receptor (GR) agonist dexamethasone (DEX) increased MAPK/ERK1/2 signaling in the presence of the noradrenergic antidepressant, desipramine (DMI), while no such effect was induced by DEX or DMI alone in human neuroblastoma SH-SY5Y cells. This enhancement was dependent on the activation of both α(2) adrenergic receptors (AR) and GR. The timing of MAPK/ERK1/2 activation as well as DEX-induced reduction in membranous α(2) AR suggests the involvement of a β-arrestin-dependent mechanism. In line with the latter, DEX increased cytosolic and decreased membranous levels of β-arrestin. Concomitantly, DEX induced a time-dependent increase in cytosolic α(2) AR-β-arrestin interaction and a decrease in β-arrestin interaction with Mdm2 E3 ubiquitin ligase. All of these effects of DEX were prevented by the GR antagonist RU486. Our data suggest an additional intracellular role for DEX, in which activation of GR interferes with the trafficking and degradation of β-arrestin-α2c-AR complex. We suggest that such an interaction in the presence of DMI can enhance MAPK/ERK1/2 signaling, a key player in neural plasticity and neurogenesis processes, which is impaired in MDD, while stimulated by antidepressants.
authors.affiliation: Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center and B. Rappaport Faculty of Medicine and B. Rappaport Research Institute, Technion IIT, POB 9649, 31096, Haifa, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Lucki
authors.forename: Ehud
authors.initials: E
authors.lastname: Klein
authors.forename: Rachel
authors.initials: R
authors.lastname: Karry
authors.forename: Dorit
authors.initials: D
authors.lastname: Ben-Shachar
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003891:Desipramine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D054875:Ubiquitination / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology; D000071557:beta-Arrestins
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000929:Antidepressive Agents, Tricyclic; D018931:Antineoplastic Agents, Hormonal; D019390:Arrestins; D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D000071557:beta-Arrestins; D015016:Yohimbine; D015735:Mifepristone; D003907:Dexamethasone; D020929:Mitogen-Activated Protein Kinase Kinases; D003891:Desipramine; D009638:Norepinephrine