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

Abstract

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.

Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain

“…Next, we explored the proposal that GABA B receptors might regulate GSK3β activity through phosphorylation of Tyr216, the auto-activation site (Cole et al, 2004; Lu et al, 2012). Figure 7 shows that rats acutely administered baclofen exhibited elevated levels of pGSK3β Tyr216 in the cortex, prefrontal cortex, caudate putamen, globus pallidus, nucleus accumbens (NAc), thalamus, and lateral septum compared to saline controls.…”

“…Whereas (Lu et al, 2012) observed phosphorylation of Ser9 in cells following in vitro treatment with a GABA B agonist, they failed to detect significant changes in phosphorylation at Tyr216. In fact, regulation of pGSK3β Tyr216 activation is most closely associated with changes in DA receptor signaling, cocaine and other stimulants readily enhance GSK3β activity, and pGSK3β mediates the development of sensitization to many effects of these stimulants (Xu et al, 2009).…”

Effect of GABA on oxidative stress in the skeletal muscles and plasma free amino acids in mice fed high‐fat diet

“…The antioxidative function of GABA was involved in GABA A (Kovacic and Somanathan, ) receptor or GABA B (Lu et al., ) receptor. The PI3K/GSK3 β /Nrf2 pathway in the latter can be activated by GABA (Lu et al., ), providing a possible antioxidative mechanism because Nrf2 (nuclear factor‐E2 related factor 2), as a key molecule balancing redox status, can enhance the transcriptions of antioxidant enzyme genes such as PRDX and Gpx (Barry and Jason, ). Nevertheless, the exact antioxidative mechanism of GABA in muscle still needs further study.…”

Clozapine Modulates the Glycogen Synthase Kinase-3 Signaling partly via GABAB Receptors

“…Using transcranial magnetic stimulation (TMS) indices of GABAergic neurotransmission, previous studies have shown lower inhibitory neurotransmission mediated by both GABAB receptors and GABAA receptors [12], while clozapine treatment significantly change the GABAB receptor-mediated inhibitory neurotransmission, but not GABAA receptor [13] suggesting that clozapine may potentiate the GABAB receptors during treatment of schizophrenia. In addition, in vivo studies reported that clozapine increased the binding affinity of GABAB receptor with its antagonist [3H]-CGP54626 [14], further highlighting GABAB receptor as a therapeutic target for clozapine.…”

“…Activation of GABAB receptors will increase the phosphorylation of GSK-3α/β (Ser21/9) via activation of Akt and this effect depends on the existence of β-arrestin [13]. Thus, we hypothesized that clozapine may modulate GSK-3 signaling via activation of GABAB receptors in the treatment of schizophrenia.…”