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 previously found that GSK3β selectively interacts with 5-HT1B 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 interaction with Giα2 and β-arrestin2 and 5-HT1BR-regulated signalings 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 5HT1BR since GSK3 inhibitors did not change the interaction between serotonin 1A receptors (5-HT1AR) and Giα2. Two GSK3 inhibitors, AR-A014418 and 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 signalings, 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.
- Serotonin
- Gi family
- cAMP
- Protein Kinases (other)
- G protein regulation
- Phosphorylation/Dephosphorylation
- Fluorescence techniques
- Received January 10, 2011.
- Revision received March 2, 2011.
- Accepted March 3, 2011.
- The American Society for Pharmacology and Experimental Therapeutics