Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action

Abstract

Dopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in clinical use. Remarkably, the effector molecules through which these medications exert their actions remain poorly characterized. Increasing attention is being focused on Akt/glycogen synthase kinase-3 (GSK-3) and wingless (Wnt) signaling pathways, which have been associated with schizophrenia in a number of genetic and postmortem studies. Antipsychotic medications may treat symptoms of psychosis, at least in part, through modulation of levels and activity of Akt, GSK-3, and Wnt-related intracellular signaling. The authors review evidence that Akt/GSK-3 and Wnt-related pathways are involved in the pathogenesis of schizophrenia as well as details of intracellular events related to these molecules mediated by both typical and atypical antipsychotic medications. Further study of Akt/GSK-3 and Wnt signaling may ultimately lead to alternative therapeutics of schizophrenia-related disorders.

Figure 1

A) Following stimulation of receptors on the plasma membrane such as receptor tyrosine kinases, PI3K generates the signaling lipid, phosphatidylinositol 3,4,5 trisphosphate (PIP₃) by phosphorylating its precursor, phosphatidylinositol 4,5 bisphosphate (PIP₂). This leads to recruitment of Akt to the plasma membrane through association with PIP₃. B) Akt is activated via phosphorylation by intracellular kinases, PDK1 and the rictor-mTORC2 complex at positions Thr 308 and Ser 473, respectively. C) Active Akt phosphorylates GSK-3 (constitutively active in its non-phosphorylated form) resulting in GSK-3 inactivation.

Figure 2

A) Phosphorylated Akt inactivates GSK-3 through phosphorylation. B) Binding of DA to the D₂ receptor leads to recruitment of β-arrestin 2, a scaffolding protein, along with Akt and the phosphatase PP2A. PP2A dephosphorylates and inactivates Akt, resulting in increased GSK-3 activity.

Figure 3

A) GSK-3 is in a complex with β-catenin, APC and Axin. In the absence of Wnt receptor activation, β-catenin is constitutively phosophorylated by GSK-3, leading to β-catenin’s degradation and thereby blocking β-catenin-mediated gene transcription. B) Binding of ligands such as Wnt to the Wnt receptor results in the formation of a complex with LRP5 or LRP6, Dvl, APC, Axin GSK-3 and Akt. Inactivation of GSK-3 via phosophorylation by Akt prevents β-catenin’s phosphorylation by GSK-3 and allows it to escape degradation. β-catenin consequently accumulates in the nucleus where it regulates transcription through interactions with DNA transcription factors.