Differential effects of antidepressants on dexamethasone-induced nuclear translocation and expression of glucocorticoid receptor.
The glucocorticoid receptor (GR) is a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Mood disorder patients often exhibit abnormalities in this axis. Although the clinical benefit of antidepressants is associated with the normalization of the disturbed HPA activity by enhanced negative feedback of the HPA axis, the precise mechanism remains unknown. In order to examine the effect of antidepressants on the translocation of GR into the nucleus, we performed time-lapse observation on SY5Y cells that had been transiently transfected with plasmids expressing the green fluorescence protein (GFP)-tagged GRalpha. Clomipramine and desipramine facilitated dexamethasone (Dex)-induced GFP-GRalpha nuclear translocation. Coincubation of verapamil, an inhibitor of membrane steroid transporters, showed little or no additive effect on GFP-GRalpha nuclear translocation induced by both Dex and clomipramine. In the absence of Dex, antidepressants did not induce the translocation of GFP-GRalpha into the nucleus. Using real-time PCR, we examined the effect of antidepressants on splicing isoform of GR, GRalpha, and GRbeta in SY5Y and Jurkat cells. Incubation with paroxetine and desipramine for 48 h and 7 days increased GRalpha expression, whereas the expression of GRbeta remained stable. Antidepressants did not alter the expression of SRp30c that is associated with alternative splicing of GR transcript. Thus, antidepressants exert differential effects on the translocation and expression of GR to enhance GR signaling.
Funato
Hiromasa
H
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan. hiromasa-funato@umin.ac.jp
Kobayashi
Ayumi
A
Watanabe
Yoshifumi
Y
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019169:Jurkat Cells; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D002121:Calcium Channel Blockers; D003907:Dexamethasone; D005938:Glucocorticoids; D049452:Green Fluorescent Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014700:Verapamil; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta