Roles of PI3K/AKT/GSK3/mTOR Pathway in Cell Signaling of Mental Illnesses

Abstract

Several pharmacological agents acting on monoamine neurotransmission are used for the management of mental illnesses. Regulation of PI3K/AKT and GSK3 pathways may constitute an important signaling center in the subcellular integration of the synaptic neurotransmission. The pathways also modulate neuronal cell proliferation, migration, and plasticity. There are evidences to suggest that inflammation of neuron contributes to the pathology of depression. Inflammatory activation of neuron contributes to the loss of glial elements, which are consistent with pathological findings characterizing the depression. A mechanism of anti-inflammatory reactions from antidepressant medications has been found to be associated with an enhancement of heme oxygenase-1 expression. This induction in brain is also important in neuroprotection and neuroplasticity. As enzymes involved in cell survival and neuroplasticity are relevant to neurotrophic factor dysregulation, the PI3K/AKT/GSK3 may provide an important signaling for the neuroprotection in depression. In this paper, we summarize advances on the involvement of the PI3K/AKT/GSK3 pathways in cell signaling of neuronal cells in mental illnesses.

Figure 1

Schematic representation of PI3K/AKT/GSK3/mTOR signaling. Examples of molecules known to act on the regulatory pathways are shown. Note that some critical pathways have been omitted for clarity.

Figure 2

Schematic structures of AKT1, PTEN, and mTOR protein. The predicted consensual domain structures for each protein are depicted. The functionally important sites including the sites of protein phosphorylation are also shown. Note that the sizes of protein are modified for clarity. PH domain: pleckstrin homology domain; C2 domain: a protein structural domain involved in targeting proteins to cell membranes; PDZ: a common structural domain in signaling proteins (PSD95, Dlg, ZO-1, etc.); HEAT: huntington, elongation factor 3, a subunit of PP2A, and TOR1; FAT: FRAP-ATM-TRRAP; FRB: FKBP12-rapamycin binding; FATC: FAT-C-terminal.

Figure 3

Potential antidepressant molecular targets based on the predominant PI3K/AKT/GSK3 pathways. Note that some critical events have been omitted for clarity. SSRI: selective serotonin reuptake inhibitors; MAOi: monoamine oxidase inhibitors; BDNF: brain-derived neurotrophic factor; 5-HT: 5-hydroxytryptamine, serotonin.