Cargando…

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

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 underst...

Descripción completa

Detalles Bibliográficos
Autores principales: Freland, Laure, Beaulieu, Jean-Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282483/
https://www.ncbi.nlm.nih.gov/pubmed/22363263
http://dx.doi.org/10.3389/fnmol.2012.00014
_version_ 1782224076172951552
author Freland, Laure
Beaulieu, Jean-Martin
author_facet Freland, Laure
Beaulieu, Jean-Martin
author_sort Freland, Laure
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3282483
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-32824832012-02-23 Inhibition of GSK3 by lithium, from single molecules to signaling networks Freland, Laure Beaulieu, Jean-Martin Front Mol Neurosci Neuroscience 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. Frontiers Media S.A. 2012-02-20 /pmc/articles/PMC3282483/ /pubmed/22363263 http://dx.doi.org/10.3389/fnmol.2012.00014 Text en Copyright © 2012 Freland and Beaulieu. http://www.frontiersin.org/licenseagreement 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.
spellingShingle Neuroscience
Freland, Laure
Beaulieu, Jean-Martin
Inhibition of GSK3 by lithium, from single molecules to signaling networks
title Inhibition of GSK3 by lithium, from single molecules to signaling networks
title_full Inhibition of GSK3 by lithium, from single molecules to signaling networks
title_fullStr Inhibition of GSK3 by lithium, from single molecules to signaling networks
title_full_unstemmed Inhibition of GSK3 by lithium, from single molecules to signaling networks
title_short Inhibition of GSK3 by lithium, from single molecules to signaling networks
title_sort inhibition of gsk3 by lithium, from single molecules to signaling networks
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282483/
https://www.ncbi.nlm.nih.gov/pubmed/22363263
http://dx.doi.org/10.3389/fnmol.2012.00014
work_keys_str_mv AT frelandlaure inhibitionofgsk3bylithiumfromsinglemoleculestosignalingnetworks
AT beaulieujeanmartin inhibitionofgsk3bylithiumfromsinglemoleculestosignalingnetworks