TY - JOUR
T1 - Glycogen synthase kinase-3β is a functional modulator of serotonin-1B receptors
AU - Chen, L.
AU - Zhou, W.
AU - Chen, P. C.
AU - Gaisina, I.
AU - Yang, S.
AU - Li, Xiaohua
PY - 2011/6
Y1 - 2011/6
N2 - 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 GSK3β 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 GSK3β in 5-HT1BR-regulated signaling, physiological function, and behaviors. Using molecular, biochemical, pharmacological, and behavioral approaches, we tested 5-HT1BR's interaction with Giα2 and β-arrestin2 and 5-HT1BR-regulated signaling in cells, serotonin release in mouse cerebral cortical slices, and behaviors in wild-type and β-arrestin2 knockout mice. Molecular ablation of GSK3β and GSK3 inhibitors abolished serotonin-induced change of 5-HT1BR coupling to Giα2 and associated signaling but had no effect on serotonin-induced recruitment of β-arrestin2 to 5-HT1BR. This effect is specific for 5-HT1BR because GSK3 inhibitors did not change the interaction between serotonin 1A receptors and Giα 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 GSK3β 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.
AB - 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 GSK3β 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 GSK3β in 5-HT1BR-regulated signaling, physiological function, and behaviors. Using molecular, biochemical, pharmacological, and behavioral approaches, we tested 5-HT1BR's interaction with Giα2 and β-arrestin2 and 5-HT1BR-regulated signaling in cells, serotonin release in mouse cerebral cortical slices, and behaviors in wild-type and β-arrestin2 knockout mice. Molecular ablation of GSK3β and GSK3 inhibitors abolished serotonin-induced change of 5-HT1BR coupling to Giα2 and associated signaling but had no effect on serotonin-induced recruitment of β-arrestin2 to 5-HT1BR. This effect is specific for 5-HT1BR because GSK3 inhibitors did not change the interaction between serotonin 1A receptors and Giα 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 GSK3β 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.
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U2 - 10.1124/mol.111.071092
DO - 10.1124/mol.111.071092
M3 - Article
C2 - 21372171
AN - SCOPUS:79956309851
SN - 0026-895X
VL - 79
SP - 974
EP - 986
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 6
ER -