Glycogen Synthase Kinase-3β Is a Functional Modulator of Serotonin-1B Receptors

Abstract

Glycogen synthase kinase-3 (GSK3) is a constitutively active protein kinase that is involved in neuronal regulation and is a potential pharmacological target of neurological disorders. We found previously that GSK3␤ selectively interacts with 5-hydroxytryptamine-1B receptors (5-HT1BR) that have important functions in serotonin neurotransmission and behavior. In this study, we provide new information supporting the importance of GSK3␤ in 5-HT1BR-regulated signaling, physiological function, and behaviors. Using molecular, biochemical, pharmacological, and behavioral approaches, we tested 5-HT1BR's interaction with G i ␣ 2 and ␤-arrestin2 and 5-HT1BR-regulated signaling in cells, serotonin release in mouse cerebral cortical slices, and behaviors in wild-type and ␤-arrestin2 knockout mice. Molecular ablation of GSK3␤ and GSK3 inhibitors abolished serotonin-induced change of 5-HT1BR coupling to G i ␣ 2 and associated signaling but had no effect on serotonin-induced recruitment of ␤-arrestin2 to 5-HT1BR. This effect is specific for 5-HT1BR because GSK3 inhibitors did not change the interaction between serotonin 1A receptors and G i ␣ 2 . Two GSK3 inhibitors, N-(4-methoxybenzyl)-NЈ-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418) and 3-(5-bromo-1-methyl-1H-indol-3-yl)-4-(benzofuran-3-yl)pyrrole-2,5-dione (BIP-135), efficiently abolished the inhibitory effect of the 5-HT1BR agonist anpirtoline on serotonin release in mouse cerebral cortical slices. GSK3 inhibitors also facilitated the 5-HT1BR agonist anpirtoline-induced behavioral effect in the tail suspension test but spared anpirtoline-induced locomotor activity. These results suggest that GSK3␤ is a functional selective modulator of 5-HT1BR-regulated signaling, and GSK3 inhibitors fine-tune the physiological and behavioral actions of 5-HT1BR. Future studies may elucidate the significant roles of GSK3 in serotonin neurotransmission and implications of GSK3 inhibitors as functional selective modulators of 5-HT1BR.

Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

“…GSK3b modulates serotonin 1-B receptors, which was observed in mouse brains (Chen et al, 2011); the antagonism of dopamine D2 receptor induces GSK3b phosphorylation as reported in rat brain (Alimohamad et al, 2005) and in human SH-SY5Y cells (Sutton and Rushlow, 2012). Also, GSK3b is associated with regulation of glutamate receptors a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPAR) and N-methyl-D-aspartate (NMDAR).…”

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…Thus, we hypothesized that changes in phosphorylation of residues at the FGF14 C-tail could affect the interaction with Nav channels. Our previous research has shown that GSK–3, a multifunctional kinase important for neuronal survival, cellular signaling, and stress response (Jope et al, 2007; Jope & Roh, 2006; Wu et al, 2013; Chen et al, 2011; Kim & Snider, 2011) and dysregulated in a number of AD and psychiatric disorders (Emamian, 2012; Jope et al, 2007; Jope & Roh, 2006; Liu et al, 2013; Budni et al, 2012; Scala et al, 2015; Maqbool et al, 2016; Morris & Berk, 2016; Provensi et al, 2016; Avila et al, 2010) affecting cognition, including depression and bipolar disorder (Gould et al, 2004; Koros & Dorner-Ciossek, 2007; Omata et al, 2011), critically modifies the interaction, assembly, localization, and activity of FGF14 and Nav channels (Hsu et al, 2015; James et al, 2015; Shavkunov et al, 2013). Furthermore, we observed that the C-tail of FGF14 contains a consensus GSK–3 phosphorylation motif ( S/T )XXX(S/T), the first residue in this sequence corresponding to S226.…”

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…80 Furthermore, there is strong evidence for a role of GSK3 in the regulation of circadian rhythm, epigenetic gene regulation 29 and 5-HT 1B receptor cell surface trafficking. 113,114 Another intriguing observation is that changes in the regulation of Akt and GSK3 activity so far are similar across different drug categories. Overall, antipsychotics, antidepressants acting on 5-HT neurotransmission and lithium have all been reported to activate Akt and inhibit GSK3 in vivo.…”