Inhibition of GSK3 by lithium, from single molecules to signaling networks

Abstract

For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects.

Keywords: Akt; arrestin; bipolar disorder; glycogen synthase kinase 3; lithium; mood stabilizer; pharmacology; protein-protein interactions.

Figure 1

Schematic representation of different direct molecular targets of lithium. These include inositol monophosphatases (IMPAs), Bisphosphate 3′-nucleotidase (BPNT), cyclooxygenase (COX), beta-arrestin 2 (βArr2), and members of the glycogen synthase kinase 3 alpha and beta (GSK3α and β). Since the mechanism by which lithium would inhibit several of these molecules is by competing with magnesium ions (Mg²⁺) acting as a co-factor we also included the possibility that other molecular targets may be affected through such competition.

Figure 2

Schematic representation of signaling pathways regulating the activity of brain GSK3 and its regulation by lithium. Activation of different cell surface receptors activates Phosphatidylinositol 3-kinases (PI3K) that in turn phosphorylates Phosphatidylinositol 4,5-bisphosphate (PIP2) into Phosphatidylinositol (3,4,5)-triphosphate (PIP3). Availability of PIP3 causes the co-recruitment of the 3-phosphoinositide dependent protein kinase-1 (PDK1) and Akt to the cell membrane and the activation of Akt by PDK1. Phosphorylation of N-terminal serine residues of glycogen synthase kinase 3 (GSK3) isoforms by activated Akt results in GSK3 inactivation. Conversely, activation of the D2 dopamine receptor (D2R) and potentially of other G protein coupled receptors (GPCR) triggers the formation of a signaling complex composed of Akt, beta-arrestin 2 (βArr2), and protein phosphatase 2A (PP2A) that results in an inactivation of Akt and concomitant relived GSK3 inhibition. Lithium can affect the equilibrium of this signaling network by inhibiting GSK3 directly and by disrupting the assembly of the Akt;βArr2;PP2A signaling complex. In addition, activated GSK3 would contribute to its own regulation by Akt by stabilizing the formation of this same protein complex.