2002]. The activation of Akt by lithium is explained, in part, by its effects on a signalling complex comprised of Akt, beta-arrestin 2(βArr2) and protein phosphatase 2A (Akt;βArr2;PP2A), as a result of competition with magnesium for Akt/ βArr2 interaction [Beaulieu et al. 2008]. The formation of the Akt;βArr2;PP2A signalling complex,

typically triggered by stimulation of the dopamine (DA) D2 receptor (D2R) by DA, normally promotes Akt dephosphorylation/inactivation [Beaulieu et al. 2005], leading to activation of GSK3 by dopamine. Rodent Inhibitors,research,lifescience,medical studies have found that lithium disrupts this signalling complex, affecting the regulation of Akt/GSK3 signalling and related behaviours, leading to enhanced Akt activity and increased inhibition of GSK3 (Figure 2) [Beaulieu et al. 2008]. This disruption occurs

within therapeutically relevant lithium concentrations (0.5–1.0 Inhibitors,research,lifescience,medical mM) [Beaulieu et al. 2008], indicating the potential clinical relevance of these findings. Figure 2. Inhibition of glycogen synthase kinase 3 (GSK3) by lithium. Lithium directly inhibits GSK3 by competitive binding for magnesium (Mg2+), disrupting the catalytic functioning of GSK3. Lithium also indirectly inhibits GSK3 by increasing serine phosphorylation, … Interestingly, recent evidence suggests that GSK3 is also Inhibitors,research,lifescience,medical able to promote its own activation, by enhancing activation of a phosphatase that removes N-terminal inhibitory phosphate groups on GSK3 [Zhang et al. 2003] and by stabilising the Akt;βArr2;PP2A signalling complex, leading to Akt dephosphorylation [O’Brien et al. 2011]. Thus, direct inhibition of GSK3 by lithium would block both mechanisms of auto-activation, providing at least two additional mechanisms by Inhibitors,research,lifescience,medical which lithium’s existing Inhibitors,research,lifescience,medical therapeutic effects can be strengthened [Freland and Beaulieu, 2012]. Furthermore, recent findings have shown that GSK-3β transcription can be decreased by lithium treatment in vitro and in vivo [Mendes et al. 2009], highlighting

the wide-ranging effects of lithium on GSK3 regulation. GSK3 inhibition is therefore an attractive hypothesis, providing a further explanation for lithium’s pharmacodynamic actions. Evidence of its therapeutic relevance is emerging from animal studies, which link GSK3 and manic- or depressive-like behaviours [Beaulieu et al. 2004; Gould et al. 2004; Kaidanovich-Beilin Montelukast Sodium et al. 2004; O’Brien et al. 2004, Prickaerts et al. 2006; Polter et al. 2010], potentially due to lithium-induced Akt activation [Pan et al. 2011]. Furthermore, abnormal GSK3 activity appears to occur in humans with depression [Karege et al. 2007; Inkster et al. 2009] and bipolar disorder [Polter et al. 2010]. Extensive evidence supports the role of GSK3 inhibition in lithium’s mechanism of action. Given the complexities of lithium pharmacodynamics, www.selleckchem.com/products/AP24534.html however, it is unlikely to be the sole therapeutic target of lithium’s mechanism of action.