Validating GSK3 as an in vivo target of lithium action.
Article Details
- CitationCopy to clipboard
O'Brien WT, Klein PS
Validating GSK3 as an in vivo target of lithium action.
Biochem Soc Trans. 2009 Oct;37(Pt 5):1133-8. doi: 10.1042/BST0371133.
- PubMed ID
- 19754466 [ View in PubMed]
- Abstract
Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Lithium directly inhibits GSK3 (glycogen synthase kinase 3), a critical regulator of multiple signal transduction pathways. Inhibition of GSK3 provides a compelling explanation for many of the known effects of lithium, including effects on early development and insulin signalling/glycogen synthesis. However, lithium also inhibits inositol monophosphatase, several structurally related phosphomonoesterases, phosphoglucomutase and the scaffolding function of beta-arrestin-2. It is not known which of these targets is responsible for the behavioural or therapeutic effects of lithium in vivo. The present review discusses basic criteria that can be applied to model systems to validate a proposed direct target of lithium. In this context, we describe a set of simple behaviours in mice that are robustly affected by chronic lithium treatment and are similarly affected by structurally diverse GSK3 inhibitors and by removing one copy of the Gsk3b gene. These observations, from several independent laboratories, support a central role for GSK3 in mediating behavioural responses to lithium.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Lithium carbonate Glycogen synthase kinase-3 beta Protein Humans UnknownNot Available Details Lithium cation Glycogen synthase kinase-3 beta Protein Humans UnknownInhibitorDetails Lithium citrate Glycogen synthase kinase-3 beta Protein Humans UnknownNot Available Details Lithium succinate Glycogen synthase kinase-3 beta Protein Humans UnknownNot Available Details