Abstract
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.
Highlights
Lithium is an alkali metal that is used medically under the form of a cationic salt Li+ in association with carbonate (COO−) or citrate
By disrupting a β-arrestin 2 (βArr2) signaling complex that is responsible for the inhibition of Akt, lithium may, have a stronger effect on glycogen synthase kinase 3 (GSK3) activity in cells in which this complex is formed. In this case, targeting this complex may confer some level of selectivity, which may explain why lithium can be useful in the treatment of bipolar disorders without significantly disrupting GSK3 mediated physiological functions in the whole organism
Some of the data reported in this review indicate that inhibition of GSK3 either directly or—more possibly—indirectly is a credible mechanism that may be responsible for some of lithium’s actions
Summary
Faculty of Medicine, Departments of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada. Edited by: Oksana Kaidanovich-Beilin, Samuel Lunenfeld Research Institute, 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. We 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.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
