Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling

Frances Fangjia Lu,Zafiris J Daskalakis,Ping Su,Fang Liu

doi:10.1186/1756-6606-5-41

Frances Fangjia Lu, Zafiris J Daskalakis + Show 2 more

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https://doi.org/10.1186/1756-6606-5-41

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Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a key mechanism in the treatment of schizophrenia. However, the downstream molecular mechanisms related to GABA potentiation remain unexplored. Recent studies have suggested that dopamine D2 receptor antagonists, which are used in the clinical treatment of schizophrenia, modulate protein kinase B (Akt)/glycogen synthase kinase (GSK)-3 signaling. Here we report that activation of GABAB receptors significantly inhibits Akt/GSK-3 signaling in a β-arrestin-dependent pathway. Agonist stimulation of GABAB receptors enhances the phosphorylation of Akt (Thr-308) and enhances the phosphorylation of GSK-3α (Ser-21)/β (Ser-9) in both HEK-293T cells expressing GABAB receptors and rat hippocampal slices. Furthermore, knocking down the expression of β-arrestin2 using siRNA abolishes the GABAB receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABAB receptor agents may exert therapeutic effects in the treatment of schizophrenia.

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Schizophrenia (SCZ) is a debilitating disorder that exacts enormous personal, social and economic costs
Clozapine treated patients demonstrated significantly longer cortical silent period (CSP) durations of large effect (i.e., Cohen’s D > 3) but no change in short interval cortical inhibition (SICI) relative to unmedicated SCZ patients and healthy subjects [9]. These findings suggest that clozapine potentiates the GABAB receptor and underscores the possibility that the GABAB receptor may play a key role in the treatment of SCZ
Activation of GABAB receptors increases phosphorylated glycogen synthase kinase (GSK)-3α/β at Ser-21/Ser-9 sites Previous studies have suggested that phosphorylation of GSK-3α/β at Ser-21/Ser-9 sites significantly decreases active site availability, inhibiting GSK-3 activity

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Introduction

Schizophrenia (SCZ) is a debilitating disorder that exacts enormous personal, social and economic costs. The human GABAB receptor gene has been localized to regions in the genome associated with schizophrenia, 6p21.3 [1,2]. The expression of the GABAB receptor has been shown to be reduced in the human schizophrenic brain [3]. The GABAB receptor agonist, baclofen has been reported to have some efficacy in SCZ patients [4]. Baclofen was shown to improve cognition in an animal model of methamphetamine-induced psychosis [5] and elicit antipsychotic-like effects in the rat paradigm of prepulse inhibition of the startle response, an animal phenotype for modeling SCZ [6]

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