Glycogen Synthase Kinase-3 is an Intermediate Modulator of Serotonin Neurotransmission

Abstract

Serotonin is a neurotransmitter with broad functions in brain development, neuronal activity, and behaviors; and serotonin is the prominent drug target in several major neuropsychiatric diseases. The multiple actions of serotonin are mediated by diverse serotonin receptor subtypes and associated signaling pathways. However, the key signaling components that mediate specific function of serotonin neurotransmission have not been fully identified. This review will provide evidence from biochemical, pharmacological, and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. In return, GSK3 directly interacts with serotonin receptors in a highly selective manner, with a prominent effect on modulating serotonin 1B receptor activity. Therefore, GSK3 acts as an intermediate modulator in the serotonin neurotransmission system, and balanced GSK3 activity is essential for serotonin-regulated brain function and behaviors. Particularly important, several classes of serotonin-modulating drugs, such as antidepressants and atypical antipsychotics, regulate GSK3 by inhibiting its activity in brain, which reinforces the importance of GSK3 as a potential therapeutic target in neuropsychiatric diseases associated with abnormal serotonin function.

Wnt Signaling in Mood and Psychotic Disorders

“…In agreement with these findings from investigating the response to antidepressant treatments that point to a key role for regulating Wnt signaling in mood behavior regulation, many clinically used drugs that affect serotonin levels, including monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), have been shown to elevate the phosphorylation levels of Ser9 and consequently decrease the GSK3β activity in vivo in mouse studies (Beaulieu, 2012;Polter and Li, 2011). In further support of a role for serotonergic signaling in the regulation of GSK3 signaling, mice with loss-of-function mutations in the serotonin biosynthesis enzyme, tryptophan hydroxylase 2 (Tph2), which results in decreased production of serotonin, display elevated GSK3β activity in the frontal cortex (Beaulieu et al, 2008b).…”

Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice

“…Here, we confirm that combined memantine and donepezil treatment improves reduced CaMKII activity in the OBX hippocampus. 5-HT receptors belong to G-protein coupled receptor family and stimulate not only CaMKII activity but also that of other kinases such as extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) [50,51,52,53], both essential for adult neurogenesis in hippocampus. Impaired adult neurogenesis may be correlated with depression-like behaviors [33,][54], and ERK and Akt phosphorylation levels are also decreased in the OBX hippocampus [43].…”

Targeting the Modulation of Neural Circuitry for the Treatment of Anxiety Disorders

“…That said, 5-HT receptors generally have the following functions (Polter and Li, 2011): 1) 5-HT 1 receptors inhibit adenyl cyclase, reduce cyclic AMP, and inhibit protein kinase A (PKA); 5-HT 1A receptors are the prototypical 5-HT 1 receptors; 2) 5-HT 2 receptors increase inositol trisphosphate, increase intracellular calcium levels, increase diacylglycerol, and activate PKA; 5-HT 2A receptors are the prototypical type 5-HT 2 receptors; 3) 5-HT 3 receptors are ligand-gated cation channels; 4) 5-HT 4 receptors activate adenyl cyclase, increase cyclic AMP, and activate PKA; 5) 5-HT 5 receptors inhibit adenyl cyclase, reduce cyclic AMP, and inhibit PKA; and 6) 5-HT 6 and 5-HT 7 receptors activate adenyl cyclase, increase cyclic AMP, and activate PKA.…”