Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder.
BACKGROUND
Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta 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 GSK3beta.


RESULTS
The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects.


CONCLUSIONS
Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.
Li
Xiaohua
X
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. xili@uab.edu
Friedman
Ari B
AB
Zhu
Wawa
W
Wang
Li
L
Boswell
Sherer
S
May
Roberta S
RS
Davis
Lori L
LL
Jope
Richard S
RS
D000328:Adult; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy / Q000503:physiopathology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018021:Lithium Chloride / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects
D018692:Antimanic Agents; D003598:Cytoskeletal Proteins; C512806:NIN protein, human; D009687:Nuclear Proteins; D010768:Phosphoserine; D018021:Lithium Chloride