Glycogen synthase kinase-3? 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)-N'-(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.

SUBMITTER: Chen L 

PROVIDER: S-EPMC3102555 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature