title: Activation of GABA(B) 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 GABA(B) receptors significantly inhibits Akt/GSK-3 signaling in a β-arrestin-dependent pathway. Agonist stimulation of GABA(B) 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 GABA(B) receptors and rat hippocampal slices. Furthermore, knocking down the expression of β-arrestin2 using siRNA abolishes the GABA(B) receptor-mediated modulation of GSK-3 signaling. Our data may help to identify potentially novel targets through which GABA(B) receptor agents may exert therapeutic effects in the treatment of schizophrenia.
authors.affiliation: Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Frances Fangjia
authors.initials: FF
authors.lastname: Lu
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Zafiris J
authors.initials: ZJ
authors.lastname: Daskalakis
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin; D000071557:beta-Arrestins
chemical_list: D000596:Amino Acids; D000730:Androstadienes; D019390:Arrestins; D047428:Protein Kinase Inhibitors; D018080:Receptors, GABA-B; D000071557:beta-Arrestins; D037342:Pertussis Toxin; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000077191:Wortmannin