- Open Access
Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling
© Lu et al.; licensee BioMed Central Ltd. 2012
- Received: 31 October 2012
- Accepted: 24 November 2012
- Published: 28 November 2012
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.
- GABAB Receptor
- Cortical Silent Period
- GABAB Receptor Agonist
- Cortical Silent Period Duration
Schizophrenia (SCZ) is a debilitating disorder that exacts enormous personal, social and economic costs. Accumulated evidence has suggested that potentiation of cortical GABAergic inhibitory neurotransmission may be a novel treatment target for resistant SCZ. The human GABAB receptor gene has been localized to regions in the genome associated with schizophrenia, 6p21.3 [1, 2]. In addition, the expression of the GABAB receptor has been shown to be reduced in the human schizophrenic brain . As well, the GABAB receptor agonist, baclofen has been reported to have some efficacy in SCZ patients . Baclofen was also shown to improve cognition in an animal model of methamphetamine-induced psychosis  and elicit antipsychotic-like effects in the rat paradigm of prepulse inhibition of the startle response, an animal phenotype for modeling SCZ .
Transcranial magnetic stimulation (TMS) indices of GABAB receptor mediated inhibitory neurotransmission can be altered through antipsychotic treatment. The cortical silent period (CSP) represents a TMS neurophysiological index of GABAB receptor mediated inhibitory neurotransmission whereas short interval cortical inhibition (SICI) represents a TMS neurophysiological index of GABAA receptor mediated inhibitory neurotransmisssion. Both the CSP and SICI were lowered in patients with SCZ [7, 8]. Clozapine treated patients demonstrated significantly longer CSP durations of large effect (i.e., Cohen’s D > 3) but no change in SICI relative to unmedicated SCZ patients and healthy subjects . These findings suggest that clozapine potentiates the GABAB receptor and also underscores the possibility that the GABAB receptor may play a key role in the treatment of SCZ. Furthermore, a recent in-vivo study by Wu et al. also confirmed these findings  which reported that the binding of the GABAB receptor antagonist 3H]-CGP54626A increased when treated with clozapine. There was a significant correlation between the clozapine dose and the increase of 3H]-CGP54626A binding in linear regression analysis. In the presence of clozapine, a left shift was shown for specific 3H]-CGP54626A binding in competition with different concentrations of GABA. Clozapine also increased 3H]-CGP54626A binding at GABAB R1 subunit when HEK293 cells overexpressed GABAB receptors, highlighting a potential therapeutic target for clozapine.
GSK-3 is a protein kinase originally identified and named for its ability to phosphorylate and inactivate the metabolic enzyme glycogen synthase . Subsequently, GSK-3 was found to be broadly involved in neural systems and modulate many aspects of neuronal function, including gene expression, neurogenesis, synaptic plasticity, neuronal structure, and neuronal death and survival [12–14]. Accumulating evidence implicates abnormal activity of GSK-3 in psychiatric disorders, such as bipolar disorder, depression, schizophrenia, ADHD and Alzheimer’s Disease [15–17] and GSK-3 is a potential protein kinase target for antipsychotics. Atypical antipsychotics, such as clozapine and olanzapine, can regulate phospho-serine-GSK-3 and inhibit its activity .
There are two highly homologous GSK-3 enzymes, GSK-3α and GSK-3β, derived from separate genes. Both GSK-3α and GSK-3β are expressed throughout the brain  and they are regulated by several mechanisms. The most well-defined regulatory mechanism is by phosphorylation of serine-9 in GSK-3β or serine-21 in GSK-3α, which inhibits GSK-3 activity [20–22]. The Akt signaling pathway often is a major regulator of GSK-3 because Akt phosphorylates GSK-3 on these inhibitory serine residues, which has been shown to involved in dopamine signaling and many aspects of psychiatric disorders . Conversely, enzymatic activity is enhanced by phosphorylation of tyrosine-216 in GSK-3β and tyrosine-279 in GSK-3α, which are autophosphorylation sites, and can facilitate substrate binding to GSK-3, although the mechanism of this modification are not well-defined .
The fact that all current antipsychotic drugs exert their effect through the blockade of dopamine D2 receptors (D2R) has established that increased D2R signaling is an important part of the pathophysiology of schizophrenia [25, 26]. Recent studies have suggested that D2R can activate the Akt/GSK-3 pathway via G protein-independent signaling [20, 27]. D2R-mediated Akt/GSK-3 regulation involves the recruitment of β-arrestin2 to the D2R and specific dephosphorylation/inactivation of the serine/threonine kinase Akt on its regulatory Thr-308 residue but not the second regulatory residue (Ser-473) . Phosphorylation of Akt in response to DA leads to a reduction of kinase activity and a concomitant activation of its substrates GSK-3α (Ser-21)/β (Ser-9) . More importantly, antipsychotics including haloperidol, clozapine and olanzapine strongly decrease recruitment of β-arrestin2 to D2R [18, 28, 29]. These data support a critical role of D2R-mediated GSK-3 signaling in the pathology of schizophrenia and suggest that antipsychotics exert their therapeutic effect by targeting GSK-3 signaling. Therefore, we investigated whether activation of GABAB receptors can modulate GSK-3 signaling. This will be a step towards establishing the relationship between the GABAB receptor and downstream targets of antipsychotic action, and potentially identifying new therapeutic targets for schizophrenia.
The cDNAs encoding human GABABR1a and GABABR2 subunits in pcDNA3 were kindly supplied by Dr. O. Carter Snead in The Hospital for Sick Children in Toronto.
The β-arrestin2 siRNA targeting human β-arrestin2 were purchased from Santa Cruz Biotechnology (cat# sc-29208).
Cell culture and transient transfection
HEK293T cells were cultured in α-MEM ( Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (Invitrogen) and maintained in incubators at 37°C, 5% CO2. HEK293T cells were grown to 90% confluence before being transiently transfected with plasmid constructs and/or siRNA using X-treme GENE 9 DNA transfection reagents (Roche). About 24–48 hours after transfection, cells were used for experiments.
Protein extracts isolation
Transfected HEK293T cells were collected, washed with 1 × PBS, and solubilized with the buffer (50 mM Tris–HCl, pH 7.5, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 2 mM EDTA, 1 mM PMSF, 1 mM Na3VO4, 4 mM NaF, 20 mM β-glycerophosphate and 5 μl/ml protease inhibitor cocktail (Sigma) and centrifuged at 10,000 g at 4°C for 10 min. The concentration of supernatant was qualified with a BCA protein assay. Finally, the samples were boiled with SDS sample buffer for 5 min, and subjected to SDS-PAGE for Western blot analysis.
Gel Electrophoresis and western blotting
Samples were separated by SDS-PAGE with 5% stacking gel and 10% separating gel and transferred to a nitrocellulose membrane. After blocking for 1 hour with 5% fat-free milk powder in TBST (10 mM Tris–HCl, 150 mM NaCl, 0.05% Tween-20, pH 7.4), blots were incubated overnight at 4 °C with primary antibodies: 1:1,000 anti-phosphorylated GSK-3α/β (Ser-21/ 9) (Cell Signaling Technology), 1:1,000 anti-GSK-3α (Cell Signaling Technology), 1:1,000 anti-GSK-3β (Cell Signaling Technology), 1:200 anti-β-arrestin2 (Santa Cruz Biotechnology), 1:10,000 anti-α-tubulin (Sigma), 1:1000 anti-GSK-3α/β (Y-279/Y-216) (Millpore), 1:1000 anti-Akt (Abcam), 1:1000 anti-phosphorylated-Akt (Thr-308) (Cell Signaling Technology), and 1:1000 anti-phosphorylated-Akt (Ser-473) (Abcam). After washes, blots were incubated with HRP-conjugated secondary antibodies (Sigma) for 2 hours at room temperature. Immunoactivity was visualized with ECL Western blot detection reagents (GE Healthcare). Data representative of three experimental replicates are shown.
All values are shown as means ± SEM. For comparisons between two groups, t-tests were performed. For comparisons of more than two groups, one-way or two-way ANOVA followed by the Student-Newman-Keuls post hoc analysis was performed.
Activation of GABAB receptors increases phosphorylated GSK-3α/β at Ser-21/Ser-9 sites
Activation of GABAB receptors has no effect on phosphorylated GSK-3α/β at Y-279/Y-216 sites
Previous studies have suggested that phosphorylation at the tyrosine-216 site of GSK-3β or tyrosine-279 of GSK-3α enhances the enzymatic activity of GSK-3. We have shown that activation of GABAB receptors may inhibit GSK-3 activity by enhancing GSK-3α/β (Ser-21/Ser-9) phosphorylation. We then tested whether activation of GABAB receptors can inhibit GSK-3 activity by inhibiting GSK-3α/β phosphorylation at the Y-279/Y-216 sites of GSK-3α/β. As shown in Figure 1C-D, activation of GABAB receptors has no effect on GSK-3α/β (Y-279/Y-216) phosphorylation. These data suggest that GABAB receptors may modulate GSK-3 activity by selectively phosphorylating GSK-3α/β at the Ser-21/Ser-9 sites.
Activation of GABAB receptors significantly enhances Akt phosphorylation at Thr-308
To further confirm the requirement of Akt activation in the GABAB receptor-mediated GSK-3 signaling, we tested whether phosphatidylinositol 3-kinases (PI3K) inhibitor can block the GABAB receptor-mediated GSK-3 phosphorylation as previous studies have shown blockade of PI3K inhibits Akt activity . As shown in Figure 2D-E, wortmannin (100 nM, 24 h), a PI3K inhibitor, block the effect of GABAB receptor on the phosphorylation of GSK3 at Ser21/Ser9 sites, further confirming the requirement of Akt in the GABAB receptor-mediated GSK-3 signaling.
GABAB receptors modulate GSK-3α/β phosphorylation through a Gi-protein-independent/ β-arrestin2-dependent pathway
We then confirmed the efficiency of β-arrestin2 siRNA for knocking-down the expression of β-arrestin2. As shown in Figure 3C, the expression of β-arrestin2 in HEK-293T cells is significantly decreased when transfected with β-arrestin2 siRNA (Santa Cruz Biotechnology), compared to cells transfected with control siRNA. We then measured the phosphorylation of GSK-3α/β (Ser-21/Ser-9) in HEK-293T cells transfected with GABAB receptors and β-arrestin2 siRNA or control siRNA. As shown in Figure 3D-E, activation of GABAB receptors significantly enhanced the phosphorylation of GSK-3α/β (Ser-21/Ser-9) in HEK-293T cells transfected with GABAB receptors and control siRNA, while activation of GABAB receptors failed to alter the phosphorylation of GSK-3α/β (Ser-21/Ser-9) in HEK-293T cells transfected with GABAB receptors and β-arrestin2 siRNA. These data indicate that β-arrestin2 is required for GABAB receptor-mediated modulation of GSK-3 signaling.
Activation of GABAB receptors increases phosphorylated GSK-3α/β at Ser-21/Ser-9 sites in rat hippocampal slices
To examine the effect of GABAB receptor on GSK-3 signaling in a relevant cellular milieu, rat hippocampal slices were utilized in parallel experiments. As shown in Figure 4A-B, pre-treatment of the hippocampal slices with the GABAB receptor specific agonist SKF97541 significantly enhanced the phosphorylation of GSK-3α/β (Ser-21/Ser-9). Consistent with the data obtained in HEK-293T cells transfected with GABAB receptors, GABAB receptor antagonist CGP52432 abolished the GABAB receptor effect on phosphorylation of GSK-3α/β (Ser-21/Ser-9). These data further confirm that GABAB receptors are involved in GSK-3 signaling.
Previous studies have suggested that GPCRs can signal without an external chemical trigger, i.e., in a constitutive or spontaneous manner . For example, dopamine D5 receptors enhance cAMP accumulation without agonist stimulation [38, 39]. Consistent with this idea, GABAB receptors also display constitutive activity as we observed a significant decrease of GSK-3α/β phosphorylation at Ser-21/Ser-9 sites treated only with the GABAB receptor antagonist CGP52432. The general physiological purpose of such basal activity may be to permit bi-direction control of receptor activity. With constitutively active pathways, the output can be either increased or decreased from a mid-range level.
GSK-3 is a multi-functional serine/threonine kinase. Its activity is regulated negatively by the phosphorylation of Ser-9 and positively by the phosphorylation of Tyr-216, a GSK-3β auto-phosphorylation site required for regulating its activity. Previous studies have shown that GSK-3β phosphorylsation at Tyr-216 can be prevented by its interaction with DISC1 (Disrupted-in-schizophrenia-1 protein) . Thus, it is possible that GABAB receptors inhibit GSK-3 activity through direct inhibition of GSK-3β phosphorylsation at Tyr-216 site. However, our results indicate that activation of GABAB receptors has no effect on GSK-3β phosphorylation at Tyr-216. Interestingly, this data is also consistent with the dopamine D2 receptor effect on GSK-3 phsphorylation as activation of D2 receptor also has no effect on GSK-3β phosphorylation at Tyr-216.
Available evidence suggests that antipsychotic drugs exert their antipsychotic effects in schizophrenia through the blockade of dopamine D2 receptors (D2R) or D2R in combination with the serotonin receptor 2A (5-HT2AR) [25, 26, 41]. GABAB receptors and D2R belong to the super family of G-protein coupled receptors (GPCRs) that exert their biological effects via intracellular G protein-coupled signaling cascades [42–45]. D2Rs display a complex pattern of signal transduction via their coupling to the Gi/Go protein. Previously, D2Rs were known to stimulate a number of signal transduction pathways including the inhibition of adenylate cyclase activity, PI (phosphatidylinositol) turnover, potentiation of arachidonic acid release, inwardly rectifying K+ and Ca2+ channels and mitogen activated protein kinases . Recently several studies have suggested that D2R can activate the Akt/GSK-3 pathway via β-arrestin2-dependent signaling. D2R-mediated Akt/GSK-3 regulation involves the recruitment of β-arrestin2 to the D2R and the formation of signaling complexes containing β-arrestin2, protein phosphatase 2A (PP2A) and Akt. Formation of this protein complex leads to specific dephosphorylation/inactivation of the serine/threonine kinase Akt on its regulatory Thr-308 residue but not the second regulatory Ser-473 residue [23, 27, 43] the inactivation of Akt, in response to DA stimulation, leads to a reduction of kinase activity and a concomitant activation of its substrates GSK-3α (Ser-21)/β (Ser-9) since both are negatively regulated by Akt . Interestingly, D2R-mediated modulation of GSK-3 signaling targets the same phosphorylation sites as GABAB receptors, but the functional effects are the opposite. The fact that antipsychotics block D2R and also antagonize the agonist-induced recruitment of β-arrestin2 to D2R , supports our contention that GABAB receptor-mediated inhibition of GSK-3 signaling may be a target for the development of novel antipsychotic medications.
- Goei VL, Choi J, Ahn J, Bowlus CL, Raha-Chowdhury R, Gruen JR: Human gamma-aminobutyric acid B receptor gene: complementary DNA cloning, expression, chromosomal location, and genomic organization. Biol Psychiatry. 1998, 44: 659-666. 10.1016/S0006-3223(98)00244-3.View ArticlePubMedGoogle Scholar
- Grifa A, Totaro A, Rommens JM, Carella M, Roetto A, Borgato L, Zelante L, Gasparini P: GABA (gamma-amino-butyric acid) neurotransmission: identification and fine mapping of the human GABAB receptor gene. Biochem Biophys Res Commun. 1998, 250: 240-245. 10.1006/bbrc.1998.9296.View ArticlePubMedGoogle Scholar
- Mizukami K, Ishikawa M, Hidaka S, Iwakiri M, Sasaki M, Iritani S: Immunohistochemical localization of GABAB receptor in the entorhinal cortex and inferior temporal cortex of schizophrenic brain. Prog Neuropsychopharmacol Biol Psychiatry. 2002, 26: 393-396. 10.1016/S0278-5846(01)00247-0.View ArticlePubMedGoogle Scholar
- Frederiksen PK: Letter: Baclofen in the treatment of schizophrenia. Lancet. 1975, 1: 702-View ArticlePubMedGoogle Scholar
- Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Kamei H, Kim HC, Yamada K: GABAB receptor agonist baclofen improves methamphetamine-induced cognitive deficit in mice. Eur J Pharmacol. 2009, 602: 101-104. 10.1016/j.ejphar.2008.10.065.View ArticlePubMedGoogle Scholar
- Bortolato M, Frau R, Orru M, Piras AP, Fa M, Tuveri A, Puligheddu M, Gessa GL, Castelli MP, Mereu G, Marrosu F: Activation of GABA(B) receptors reverses spontaneous gating deficits in juvenile DBA/2J mice. Psychopharmacology (Berl). 2007, 194: 361-369. 10.1007/s00213-007-0845-5.View ArticleGoogle Scholar
- Wobrock T, Schneider M, Kadovic D, Schneider-Axmann T, Ecker UK, Retz W, Rosler M, Falkai P: Reduced cortical inhibition in first-episode schizophrenia. Schizophr Res. 2008, 105: 252-261. 10.1016/j.schres.2008.06.001.View ArticlePubMedGoogle Scholar
- Daskalakis ZJ, Christensen BK, Chen R, Fitzgerald PB, Zipursky RB, Kapur S: Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation. Arch Gen Psychiatry. 2002, 59: 347-354. 10.1001/archpsyc.59.4.347.View ArticlePubMedGoogle Scholar
- Shi-Kai L, Paul BF, Mellisa D, Chen R, Dashalakis ZJ: The relationship between cortical inhibition, antipsychotic treatment, ans th symptoms of schizophrenia. Biol Psychiatry. 2009, 85: 503-509.Google Scholar
- Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, Snead OC: Evidence that clozapine directly interacts on the GABAB receptor. Neuroreport. 2011, 22: 37-41.View ArticleGoogle Scholar
- Embi N, Rylatt DB, Cohen P: Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980, 107: 519-527.View ArticlePubMedGoogle Scholar
- Doble BW, Woodgett JR: GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci. 2003, 116: 1175-1186. 10.1242/jcs.00384.PubMed CentralView ArticlePubMedGoogle Scholar
- Frame S, Cohen P: GSK3 takes centre stage more than 20 years after its discovery. Biochem J. 2001, 359: 1-16. 10.1042/0264-6021:3590001.PubMed CentralView ArticlePubMedGoogle Scholar
- Jope RS, Johnson GV: The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004, 29: 95-102. 10.1016/j.tibs.2003.12.004.View ArticlePubMedGoogle Scholar
- Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA. 1996, 93: 8455-8459. 10.1073/pnas.93.16.8455.PubMed CentralView ArticlePubMedGoogle Scholar
- Medina M, Avila J: Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer's disease. Curr Pharm Des. 2010, 16: 2790-2798. 10.2174/138161210793176581.View ArticlePubMedGoogle Scholar
- Amar S, Belmaker RH, Agam G: The possible involvement of glycogen synthase kinase-3 (GSK-3) in diabetes, cancer and central nervous system diseases. Curr Pharm Des. 2011, 17: 2264-2277. 10.2174/138161211797052484.View ArticlePubMedGoogle Scholar
- Li X, Rosborough KM, Friedman AB, Zhu W, Roth KA: Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. Int J Neuropsychopharmacol. 2007, 10: 7-19. 10.1017/S1461145706006547.View ArticlePubMedGoogle Scholar
- Yao HB, Shaw PC, Wong CC, Wan DC: Expression of glycogen synthase kinase-3 isoforms in mouse tissues and their transcription in the brain. J Chem Neuroanat. 2002, 23: 291-297. 10.1016/S0891-0618(02)00014-5.View ArticlePubMedGoogle Scholar
- Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG: Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA. 2004, 101: 5099-5104. 10.1073/pnas.0307921101.PubMed CentralView ArticlePubMedGoogle Scholar
- Chalecka-Franaszek E, Chuang DM: Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA. 1999, 96: 8745-8750. 10.1073/pnas.96.15.8745.PubMed CentralView ArticlePubMedGoogle Scholar
- De Sarno P, Li X, Jope RS: Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology. 2002, 43: 1158-1164. 10.1016/S0028-3908(02)00215-0.View ArticlePubMedGoogle Scholar
- Beaulieu JM, Marion S, Rodriguiz RM, Medvedev IO, Sotnikova TD, Ghisi V, Wetsel WC, Lefkowitz RJ, Gainetdinov RR, Caron MG: A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell. 2008, 132: 125-136. 10.1016/j.cell.2007.11.041.View ArticlePubMedGoogle Scholar
- Beurel E, Jope RS: The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol. 2006, 79: 173-189. 10.1016/j.pneurobio.2006.07.006.PubMed CentralView ArticlePubMedGoogle Scholar
- Seeman P: Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets. 2006, 10: 515-531. 10.1517/14728126.96.36.1995.View ArticlePubMedGoogle Scholar
- Seeman P, Lee T: Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science. 1975, 188: 1217-1219. 10.1126/science.1145194.View ArticlePubMedGoogle Scholar
- Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG: An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005, 122: 261-273. 10.1016/j.cell.2005.05.012.View ArticlePubMedGoogle Scholar
- Alimohamad H, Rajakumar N, Seah YH, Rushlow W: Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry. 2005, 57: 533-542. 10.1016/j.biopsych.2004.11.036.View ArticlePubMedGoogle Scholar
- Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR, Caron MG: Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. Proc Natl Acad Sci USA. 2008, 105: 13656-13661. 10.1073/pnas.0803522105.PubMed CentralView ArticlePubMedGoogle Scholar
- Russell JC, Kishimoto K, O’Driscoll C, Hossain MA: Neuronal pentraxin 1 induction in hypoxic-ischemic neuronal death is regulated via a glycogen synthase kinase-3alpha/beta dependent mechanism. Cell Signal. 2011, 23: 673-682. 10.1016/j.cellsig.2010.11.021.PubMed CentralView ArticlePubMedGoogle Scholar
- Gjoni T, Urwyler S: Changes in the properties of allosteric and orthosteric GABAB receptor ligands after a continuous, desensitizing agonist pretreatment. Eur J Pharmacol. 2009, 603: 37-41. 10.1016/j.ejphar.2008.12.014.View ArticlePubMedGoogle Scholar
- Bongers G, Sallmen T, Passani MB, Mariottini C, Wendelin D, Lozada A, Marle A, Navis M, Blandina P, Bakker RA, Panula P, Leurs R: The Akt/GSK-3beta axis as a new signaling pathway of the histamine H(3) receptor. J Neurochem. 2007, 103: 248-258.PubMedGoogle Scholar
- Martelli AM, Chiarini F, Evangenlisti C, Cappellini A, Buontempo F, Bressanin D, Fini M, McCubrey JA: Two hits are better than one: targeting both phosphatidylinositol 3-kinas and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 2012, 3 (4): 371-394.PubMed CentralView ArticlePubMedGoogle Scholar
- Campa VM, Kypta RM: Issues associated with the use of phosphospecific antibodies to localise active and inactive pools of GSK-3 in cells. Biol Direct. 2011, 6: 4-10.1186/1745-6150-6-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Arai S, Takuma K, Mizoguchi H, Ibi D, Nagai T, Takahashi K, Kamei H, Nabeshima T, Yamada K: Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen. Neuropsychopharmacology. 2008, 33: 3164-3175. 10.1038/npp.2008.41.View ArticlePubMedGoogle Scholar
- Smit MJ, Vischer HF, Bakker RA, Jongejan A, Timmerman H, Pardo L, Leurs R: Pharmacogenomic and structural analysis of constitutive g protein-coupled receptor activity. Annu Rev Pharmacol Toxicol. 2007, 47: 53-87. 10.1146/annurev.pharmtox.47.120505.105126.View ArticlePubMedGoogle Scholar
- Beaulieu J-M, Geinetdinov RR, Caron MG: The Akt-GSK-3 sinaling cascade in the actions of dopamine. Trends Pharmacol Sci. 2007, 28 (4): 166-172. 10.1016/j.tips.2007.02.006.View ArticlePubMedGoogle Scholar
- Demchyshyn LL, McConkey F, Niznik HB: Dopamine D5 receptor agonist high affinity and constitutive activity profile conferred by carboxyl-terminal tail sequence. J Biol Chem. 2000, 275: 23446-23455. 10.1074/jbc.M000157200.View ArticlePubMedGoogle Scholar
- Plouffe B, D’Aoust JP, Laquerre V, Liang B, Tiberi M: Probing the constitutive activity among dopamine D1 and D5 receptors and their mutants. Methods Enzymol. 2010, 484: 295-328.View ArticlePubMedGoogle Scholar
- Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH: Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009, 136: 1017-1031. 10.1016/j.cell.2008.12.044.PubMed CentralView ArticlePubMedGoogle Scholar
- Tyson PJ, Roberts KH, Mortimer AM: Are the cognitive effects of atypical antipsychotics influenced by their affinity to 5HT-2A receptors?. Int J Neurosci. 2004, 114: 593-611. 10.1080/00207450490430552.View ArticlePubMedGoogle Scholar
- Missale C, Nash SR, Robinson SW, Jaber M, Caron MG: Dopamine receptors: from structure to function. Physiol Rev. 1998, 78: 189-225.PubMedGoogle Scholar
- Strange PG: Studies on the structure and function of D2-dopamine receptors. Biochem Soc Trans. 1992, 20: 126-130.View ArticlePubMedGoogle Scholar
- Vallone D, Picetti R, Borrelli E: Structure and function of dopamine receptors. Neurosci Biobehav Rev. 2000, 24: 125-132. 10.1016/S0149-7634(99)00063-9.View ArticlePubMedGoogle Scholar
- Pinard A, Seddik R, Bettler B: GABAB receptors: physiological functions and mechanisms of diversity. Adv Pharmacol. 2010, 58: 231-255.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.