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.

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

“…Like resveratrol in the present study, high frequency stimulation can induce AKT Thr308 phosphorylation, without affecting total protein levels (Tsokas et al, 2007; though see Sui et al, 2008). AKT function has been associated with prefrontal cortex structural alterations in both humans and mice (Lai et al, 2006;Tan et al, 2008), together with alterations in social information processing and mental health conditions associated with disordered mood, such as depression, autism, bipolar disorder and schizophrenia (De Lacy and King, 2013;Ebert and Greenberg, 2013;Emamian, 2012;Kitagishi et al, 2012;Marsden, 2013;Zheng et al, 2012). Resveratrol increased Thr308 phosphorylation of AKT, noteworthy as the brains of depressed (suicide and non-suicide) subjects exhibit prefrontal cortex reductions in AKT enzymatic activity, including Thr308 phosphorylation, and also in the absence of protein level changes (Dwivedi et al, 2010;Kar ege et al, 2011Kar ege et al, , 2007.…”

Apoptotic Effects and Cell Cycle Arrest Effects of Extracts from Cnidium monnieri (L.) Cusson through Regulating Akt/mTOR/GSK-3β Signaling Pathways in HCT116 Colon Cancer Cells

“…Protein kinase B (PKB/Akt)는 암세포의 성장과 증식에 중 요한 역할을 하는 것으로 알려져 있으며, mammalian target of rapamycin (mTOR)나 p53, Glycogen Synthase kinase-3β (GSK-3β)과 같은 중요 신호분자들을 조절한다 [1,9,15]. p-Akt 는 Tuberous Sclerosis 2 (TSC2)를 인산화시킴으로써 mTOR의 활성을 조절하며, GSK-3β의 Serine9 자리에 인산기를 붙여 비활성화 시킨다 [15].…”

“…p-Akt 는 Tuberous Sclerosis 2 (TSC2)를 인산화시킴으로써 mTOR의 활성을 조절하며, GSK-3β의 Serine9 자리에 인산기를 붙여 비활성화 시킨다 [15]. 비활성화된 GSK-3β는 β-catenin를 분해 시키지 못하고, 이로 인하여 세포질에 축적된 β-catenin은 핵 안으로 들어가서 세포의 증식과 생존에 필요한 여러 유전자들 을 전사시킨다 [4].…”

Regulation of Pain in Fibromyalgia by Selective Serotonin and Serotonin Norepinephrine Reuptake Inhibition

“…In addition to the well-characterized components of the 5-HT signaling system which defined the role of the serotonin G-proteincoupled receptors [44,52], activation of cyclic AMP-dependent protein kinase A (PKA), phosphorylation of cyclic AMP responsive element binding protein [44] and activation of Ca [54][55][56] through G-coupled signaling [55]. However, what remains conjectural is whether activation of JAK-2/STAT-3, ERK1/2 or PI3K/Akt which had been proposed as a mechanism pertinent to neuroprotection in depressive disorders [54] was also critical for blunting chronic pain in FMS.…”

“…However, what remains conjectural is whether activation of JAK-2/STAT-3, ERK1/2 or PI3K/Akt which had been proposed as a mechanism pertinent to neuroprotection in depressive disorders [54] was also critical for blunting chronic pain in FMS.…”