title: Glycogen synthase kinase-3β is critical for interferon-α-induced serotonin uptake in human Jurkat T cells.
abstract: Dysregulation of glycogen synthase kinase (GSK)-3β contributes to the pathophysiology of mood disorders. However, how its regulation is responsible for the functioning of serotonin (5-HT) requires further investigation. Although enhancement of T-cell function may present an alternative strategy to treat depression, the precise mechanisms have yet to be established. Our previous studies have found that interferon-alpha (IFN-α) up-regulates serotonin transporter (5-HTT) expression and induces 5-HT uptake in T cells. The present study is to examine GSK-3β regulation on IFN-α-induced 5-HTT functions. GSK-3β short hairpin RNAs (shRNAs) or GSK-3β inhibitors decreased IFN-α-induced 5-HT uptake and 5-HTT expression. Src activation and calcium/calcium-activated calmodulin kinase II (CaMKII) were involved in IFN-α-induced phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) (Tyr402) and GSK-3β (Tyr216), which regulated 5-HT uptake. GSK-3β knockdown blocked the IFN-α-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and signal transducer and transactivator (STAT) 1. In addition to inhibiting ERK, a selective 5-HTT inhibitor fluoxetine blocked IFN-α-induced activations of Src, CaMKII-regulated Pyk2/GSK-3β cascade, as well as STAT1 activation and translocation. These results indicated that calcium/CaMKII- and Src-regulated Pyk2 participated in IFN-α-induced GSK-3β activation and GSK-3β-regulated 5-HT uptake. GSK-3β signaling facilitated IFN-α-activated STAT1 by regulating ERK1/2, which controlled 5-HT uptake. Fluoxetine interfered with the Pyk2/GSK-3β cascade, thereby inhibiting IFN-α-induced 5-HT uptake.
authors: Department of Nursing, Chung Hwa University of Medical Technology, Tainan County, Taiwan. tcwhmy@ms58.hinet.net
authors: Chiung-Wen
authors: CW
authors: Tsao
authors: Chiou-Feng
authors: CF
authors: Lin
authors: Hung-Tsung
authors: HT
authors: Wu
authors: Ching-Ting
authors: CT
authors: Ma
authors: Wei-Ching
authors: WC
authors: Huang
authors: Chia-Yuan
authors: CY
authors: Hsieh
authors: Pui-Ching
authors: PC
authors: Choi
authors: Kung-Chia
authors: KC
authors: Young
mesh_terms: D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003863:Depression / Q000139:chemically induced / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000009:adverse effects / Q000494:pharmacology*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000494:pharmacology*; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034622:RNA Interference; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020536:Enzyme Activators; D051418:Focal Adhesion Kinase 2; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D019061:src-Family Kinases; C493230:SLC6A4 protein, human; C494079:STAT1 protein, human; C103547:PTK2B protein, human; C000605506:GSK3B protein, human; C535150:MAPK1 protein, human