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Lithium Takes Indirect Route to Inhibit GSK-3β

Adapted from a story that originally appeared on the Alzheimer Research Forum.

20 January 2008. Lithium is an old and valued drug for mood disorders, whose mechanism of action remains murky. Inhibition of the glycogen synthase kinase 3 β (GSK-3β) has been implicated, but lithium inhibits this enzyme only weakly and requires much higher concentrations to block it in vitro than to elicit a therapeutic effect in vivo. Now, work from the lab of Marc Caron at Duke University Medical Center, Durham, North Carolina, published in the January 11 issue of Cell, shows that lithium can inhibit GSK-3 in vivo, but does so indirectly. It disrupts its signaling through the upstream kinase Akt. Specifically, lithium breaks up a magnesium-dependent association of Akt with the scaffolding protein β-arrestin 2 (β-ARR2). That results in activation of Akt, which then phosphorylates and inhibits GSK-3β.

There are some provisional links between members of this pathway and schizophrenia, including genetic association studies implicate AKT1 as a susceptibility gene (see SchizophreniaGene entry), and studies that suggest that antipsychotic drugs regulate Akt/GSK-3β signaling (e.g., Roh et al., 2007; Li et al., 2007; SRF related news story).

First author Jean-Martin Beaulieu used β-arrestin 2 (βARR2) knockout mice to probe the role of this scaffolding protein in lithium action. βARR2 organizes a signaling complex on G protein-coupled receptors that includes the Akt kinase. The complex does not require G proteins for activity, and thus represents an alternative signaling pathway utilized by GPCRs. Beaulieu and colleagues show that lithium injection into the striatum of mice led to activation of Akt and the subsequent inactivation of GSK-3β kinase. Lithium had no such effect in βARR2 knockout mice, nor did the mice show the expected behavioral effects of lithium treatment. The knockout mice were also refractory to chronic changes in the activity of Akt or GSK-3, and associated expression of the β-catenin gene, upon prolonged lithium treatment.

In-vitro immunoprecipitation studies showed that βARR2 was required to see interaction of Akt with protein phosphatase 2A in a signaling complex. Lithium prevented the association of Akt with βARR2 or Akt and two different subunits of PP2A. A similar effect was seen in vivo. Lithium broke up the complex by competing with magnesium, which was required for the interaction. Importantly, all these effects occurred at concentrations of lithium that are attained therapeutically. The effects of lithium appeared specific to the GPCR-mediated regulation of the Akt pathway, and the drug did not interfere with other functions of either βARR2 or G protein-dependent receptor signaling. The results indicate that lithium may not generally inhibit the pathway, but instead offers a means of precisely targeting selective GPCR functions that rely on arrestin-containing signaling complexes.

These pathways are not currently front and center in schizophrenia research, but several groups, in particular the laboratories of Joseph Gogos and Maria Karayiorgou at Columbia University, New York, have investigated the role of AKT in both schizophrenia etiology and antipsychotic drug effects (see SRF related news story). And, as Beaulieu and colleagues point out, lithium is used to enhance the effects of antipsychotic drugs in refractory cases. "Identification of the Akt:bArr2:PP2A signaling complex as a molecular target of lithium thus provides a mechanism by which this pharmacological agent may enhance the actions of other drugs acting through Akt/GSK3 signaling by preventing the inhibition of Akt by PP2A," they write.—Pat McCaffrey.

Beaulieu J, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG. A b-arrestin 2 Signaling Complex Mediates Lithium Action on Behavior. Cell. 2008 Jan 11;132:125-136. Abstract

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