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Glycogen synthase kinase‐3β is critical for Interferon‐α‐induced serotonin uptake in human Jurkat T cells
Author(s) -
Tsao ChiungWen,
Lin ChiouFeng,
Wu HungTsung,
Ma ChingTing,
Huang WeiChing,
Hsieh ChiaYuan,
Choi PuiChing,
Young KungChia
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22994
Subject(s) - gsk 3 , gsk3b , microbiology and biotechnology , serotonin transporter , kinase , chemistry , signal transduction , tyrosine phosphorylation , proto oncogene tyrosine protein kinase src , biology , serotonin , biochemistry , receptor
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. J. Cell. Physiol. 227: 2556–2566, 2012. © 2011 Wiley Periodicals, Inc.