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. Because of changes in these neurotransmitter systems and the actions of therapeutic drugs GSK3 has been linked to the mood disorders bipolar Rabbit polyclonal to AnnexinVI. disorder and depressive disorder 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 depressive disorder 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 nerve-racking 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. phosphorylation of the N-terminal serine. Tyrosine phosphorylation of GSK3 (Tyr216-GSK3β ; Tyr279-GSK3α ) also contributes to regulating its activity in an activating manner but the mediating kinases remain to be clearly recognized and this modification may be carried out by autophosphorylation so its importance in regulating the activity of GSK3 in situ remains a matter of debate . Fig 1 PF-04880594 Regulation of the inhibitory serine-phosphorylation of GSK3 Further substrate-selective regulation of the actions of GSK3 is also needed because GSK3 phosphorylates more than 40 substrates . This large number of substrates enables GSK3 to influence many critical cellular functions such as gene expression cell structure neural plasticity and survival so regulatory mechanisms must be invoked to selectively alter GSK3 activity to limit the substrates that it phosphorylates. GSK3-binding proteins provide one method by which cells have developed substrate-selective regulation of GSK3 (Fig. 2A). For example in the Wnt signaling pathway axin and other proteins bind GSK3 to direct its actions to a specific substrate β -catenin [6 7 Recently several additional GSK3-binding proteins have PF-04880594 been identified and it appears that this is a common mechanism by which the action of GSK3 is directed to specific substrates . Fig 2 Mechanisms contributing to substrate-selective regulation of GSK3 Another method by which the capacity of GSK3 to interact with substrates is limited is by regulation of its subcellular localization (Fig. 2B). For example nuclear levels of GSK3 are dynamically regulated with changes in the nuclear GSK3 level evident in several conditions and this affects its ability to phosphorylate nuclear substrates such as certain transcription factors [8-10]. There also appears to be subcellular compartment-selective phosphorylation of the inhibitory serine of GSK3 to locally modulate its activity such PF-04880594 as following activation of signals to the mitochondria which can target mitochondrial GSK3 . Thus subcellular-selective changes in the localization PF-04880594 and phosphorylation of GSK3 can serve to regulate its actions on substrates within these compartments. Finally GSK3’s actions are often regulated by the phosphorylation state of its substrate because most of GSK3’s substrates must be ‘primed’ pre-phosphorylated at a residue four-amino acids removed from the GSK3 phosphorylating site (Fig. 2C). Thus the activity of a signaling pathway leading to the phosphorylation of the primed site of a substrate regulates the ability of GSK3 to phosphorylate the primed substrate. This in concert with the other three regulatory mechanisms (phosphorylation protein complexes localization) combines to provide an integrated control to allow local and substrate-specific regulation of the actions of GSK3 . In other words GSK3 needs to be in the right phosphorylation state in the right place and associated with the right protein partners at the same time that a substrate is co-localized and primed by another signaling pathway. Because of these multiple regulatory mechanisms many proteins can be targets of phosphorylation by GSK3 in a selective manner. The activity of GSK3 also can be regulated pharmacologically. Since GSK3 is a key component of many fundamental neuronal processes as discussed later in this article it was very intriguing when Klein and Melton  discovered that the PF-04880594 therapeutic agent lithium is a direct inhibitor of GSK3. This raised the hypothesis that inhibition of GSK3 is important in the therapeutic actions of lithium as.