Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

Xiaohua Li, Ari B. Friedman, Wawa Zhu, Li Wang, Sherer Boswell, Roberta S. May, Lori L. Davis, Richard S Jope

Research output: Contribution to journalArticle

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Abstract

Background: Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK3β). The mood stabilizer lithium inhibits GSK3β in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3β in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. Methods: The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3β. Results: The level of phospho-Ser9-GSK3β in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3β and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3β levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. Conclusions: Signaling pathways regulating serine9-phosphorylation of GSK3β can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3β in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3β in human PBMCs may provide a biochemical marker to evaluate the association between GSK3β inhibition and therapeutic responses to lithium treatment.

Original languageEnglish
Pages (from-to)216-222
Number of pages7
JournalBiological Psychiatry
Volume61
Issue number2
DOIs
StatePublished - Jan 15 2007
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Bipolar Disorder
Lithium
Blood Cells
Therapeutics
Healthy Volunteers
Multifunctional Enzymes
Phosphorylation
Phosphoric Monoester Hydrolases
Phosphotransferases
Biomarkers

Keywords

  • Bipolar disorder
  • GSK3
  • lithium
  • PBMC

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells : Implication in the Treatment of Bipolar Disorder. / Li, Xiaohua; Friedman, Ari B.; Zhu, Wawa; Wang, Li; Boswell, Sherer; May, Roberta S.; Davis, Lori L.; Jope, Richard S.

In: Biological Psychiatry, Vol. 61, No. 2, 15.01.2007, p. 216-222.

Research output: Contribution to journalArticle

Li, Xiaohua ; Friedman, Ari B. ; Zhu, Wawa ; Wang, Li ; Boswell, Sherer ; May, Roberta S. ; Davis, Lori L. ; Jope, Richard S. / Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells : Implication in the Treatment of Bipolar Disorder. In: Biological Psychiatry. 2007 ; Vol. 61, No. 2. pp. 216-222.
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AB - Background: Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK3β). The mood stabilizer lithium inhibits GSK3β in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3β in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. Methods: The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3β. Results: The level of phospho-Ser9-GSK3β in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3β and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3β levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. Conclusions: Signaling pathways regulating serine9-phosphorylation of GSK3β can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3β in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3β in human PBMCs may provide a biochemical marker to evaluate the association between GSK3β inhibition and therapeutic responses to lithium treatment.

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