Glycogen Synthase Kinase-3 (GSK3) in Psychiatric Diseases and Therapeutic Interventions

Abstract

Glycogen synthase kinase-3 (GSK3) has recently been linked to mood disorders and schizophrenia, and the neurotransmitter systems and therapeutic treatments associated with these diseases. GSK3 is a widely influential enzyme that is capable of phosphorylating, and thereby regulating, over forty known substrates. Four mechanisms regulating GSK3 (phosphorylation, protein complexes, localization, and substrate phosphorylation) combine to provide substrate-specific regulation of the actions of GSK3. Several intracellular signaling cascades converge on GSK3 to modulate its activity, and several neurotransmitter systems also regulate GSK3, including serotonergic, dopaminergic, cholinergic, and glutamatergic systems. Because of changes in these neurotransmitter systems and the actions of therapeutic drugs, GSK3 has been linked to the mood disorders, bipolar disorder and depression, and to schizophrenia. Inhibition of GSK3 may be an important therapeutic target of mood stabilizers, and regulation of GSK3 may be involved in the therapeutic effects of other drugs used in psychiatry. Dysregulated GSK3 in bipolar disorder, depression, and schizophrenia could have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression, and the ability of neurons to respond to stressful, potentially lethal, conditions. In part because of these key actions of GSK3 and its associations with mood disorders and schizophrenia, much research is currently being devoted to identifying new selective inhibitors of GSK3.

Population-based linkage analysis of schizophrenia and bipolar case–control cohorts identifies a potential susceptibility locus on 19q13

“…17 GSK3B activity is inhibited by lithium and has been implicated in schizophrenia and bipolar disorder by a number of different approaches, and remains a target of interest in psychiatry drug discovery. 18,19 Another candidate gene in the region, glutamate Population-based linkage; bipolar and schizophrenia C Francks et al receptor, ionotropic, kainate 5 (GRIK5), forms functional heteromeric kainite preferring ionic channels in combination with other GRIK subunit genes, 16 and its close homolog GRIK4 has been implicated in schizophrenia and bipolar disorder by genetic and cytogenetic analysis. 20 GSK3A and GRIK5 are both strong candidates for future mutation analysis in bipolar disorder and schizophrenia.…”

Circadian genes, rhythms and the biology of mood disorders

“…These behaviors are reminiscent of bipolar patients in the manic state. This is perhaps not surprising since lithium treatment is known to inhibit the actions of GSK3β (Jope and Roh, 2006). Besides its role in circadian rhythms, GSK3β is a widely expressed kinase that has many functions in the brain (Jope and Roh, 2006).…”

“…This is perhaps not surprising since lithium treatment is known to inhibit the actions of GSK3β (Jope and Roh, 2006). Besides its role in circadian rhythms, GSK3β is a widely expressed kinase that has many functions in the brain (Jope and Roh, 2006). Furthermore, it is unclear as to what brain region is involved in the manic-like behaviors since the transgene is expressed in several regions, or if this overexpression affects circadian rhythms or the regulation of circadian genes (Spittaels et al, 2002).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…Nonetheless, improved understanding of the intracellular substrates of lithium action might allow for the design of lithiummimics that avoid its adverse effects (Table 4). [223][224][225] Notably, by both direct and upstream (indirect) actions, lithium interferes with the activity (phosphorylation status) of glycogen synthase kinase-3␤ (GSK-3␤), a highly regulated, constitutively active, and ubiquitous modulator of many proteins which is itself deactivated by phosphorylation. 9,[223][224][225] Whether GSK-3 exerts a negative influence on mood per se is unclear, but several classes of antidepressant phosphorylate (deactivate) GSK-3␤, as does electroconvulsive therapy.…”

“…[223][224][225] Notably, by both direct and upstream (indirect) actions, lithium interferes with the activity (phosphorylation status) of glycogen synthase kinase-3␤ (GSK-3␤), a highly regulated, constitutively active, and ubiquitous modulator of many proteins which is itself deactivated by phosphorylation. 9,[223][224][225] Whether GSK-3 exerts a negative influence on mood per se is unclear, but several classes of antidepressant phosphorylate (deactivate) GSK-3␤, as does electroconvulsive therapy. [223][224][225][226] Furthermore, facilitation of the mood-improving actions of antidepressant by zinc may reflect an inhibitory influence on GSK-3␤, 227 and GSK-3␤ inhibitors display antidepressant properties in rodent models.…”