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Front. Mol. Neurosci., 20 February 2012 | http://dx.doi.org/10.3389/fnmol.2012.00014

Inhibition of GSK3 by lithium, from single molecules to signaling networks

  • Faculty of Medicine, Departments of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada

For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects.

Keywords: lithium, glycogen synthase kinase 3, arrestin, Akt, mood stabilizer, bipolar disorder, pharmacology, protein-protein interactions

Citation: Freland L and Beaulieu J (2012) Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front. Mol. Neurosci. 5:14. doi: 10.3389/fnmol.2012.00014

Received: 16 January 2012; Paper pending published: 27 January 2012;
Accepted: 31 January 2012; Published online: 20 February 2012.

Edited by:

Oksana Kaidanovich-Beilin, Samuel Lunenfeld Research Institute, Canada

Reviewed by:

Richard S. Jope, University of Alabama at Birmingham, USA
Jim R. Woodgett, Mount Sinai Hospital, Canada

Copyright: © 2012 Freland and Beaulieu. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

*Correspondence: Jean-Martin Beaulieu, Faculty of Medicine, Departments of Psychiatry and Neuroscience, Université Laval-IUSMQ, 2601 Chemin de la Canardière, Suite F-6500, Beauport (Québec), QC G1J 2G3, Canada. e-mail: martin.beaulieu@crulrg.ulaval.ca