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  • The International Journal of Neuropsychopharmacology, Volume 11, Issue 2
  • March 2008, pp. 197-205

Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia

  • Shirly Amar (a1), Galit Shaltiel (a1), Liad Mann (a1), Alon Shamir (a1), Brian Dean (a2), Elizabeth Scarr (a2), Yuly Bersudsky (a1), R. H. Belmaker (a1) and Galila Agam (a1)
  • DOI: http://dx.doi.org/10.1017/S1461145707007948
  • Published online: 06 August 2007
Abstract
Abstract

Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and β-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3β, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3β. Prolonged DRD2 activation leads to its ‘desensitization’ which involves GRKs and β-arrestins. β-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, β-arrestin1, AKT1 and GSK-3β are involved in the pathophysiology of schizophrenia. Lymphocytes obtained from schizophrenia and bipolar patients and healthy controls recruited from the Beer-Sheva Mental Health Center were transformed by Epstein–Barr virus (EBV) into lymphocyte-derived cell lines (LDCL). Post-mortem brain samples were obtained from the Rebecca L. Cooper Brain Bank, Parkville, Australia. The study was approved by the IRB committees of Beer-Sheva, Israel and Parkville, Australia. Levels of the specific proteins were assayed by Western blotting. β-arrestin1 protein levels were significantly ~2-fold increased in LDCL from schizophrenia patients while Par-4 protein levels were unaltered. A 63% significant decrease was found in frontal cortex phospho-Ser9-GSK-3β protein levels in schizophrenia but not in those of AKT1, Par-4 or β-arrestin1. Elevated β-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3β protein levels in post-mortem frontal cortex of schizophrenia patients vs. control groups support the possible involvement of these proteins in the pathophysiology of schizophrenia. However, since we did not find differences in β-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3β participates in other signalling cascades we can not rule out the possibility that the differences found reflect deviation in DRD2 signalling.

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Corresponding author
Address for correspondence: G. Agam, Ph.D., Stanley Research Center and Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 4600 Beer-Sheva 84170, Israel. Tel.: +972-8-6401737Fax: +972-8-6401740E-mail: galila@bgu.ac.il
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H Alimohamad , L Sutton , J Mouyal , N Rajakumar , WJ Rushlow (2005). The effects of antipsychotics on beta-catenin, glycogen synthase kinase-3 and dishevelled in the ventral midbrain of rats. Journal of Neurochemistry 95, 513525.

S Amar , BC Jones , C Nadri , N Kozlovsky , RH Belmaker , G Agam (2004). Genetic correlational analysis of glycogen synthase kinase-3 beta and prepulse inhibition in inbred mice. Genes, Brain & Behavior 3, 178180.

S Avissar , A Matuzany-Ruban , K Tzukert , G Schreiber (2004). Beta-arrestin-1 levels: reduced in leukocytes of patients with depression and elevated by antidepressants in rat brain. American Journal of Psychiatry 161, 20662072.

C Beasley , D Cotter , N Khan , C Pollard , P Sheppard , I Varndell , S Lovestone , B Anderton , I Everall (2001). Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neuroscience Letters 302, 117120.

JM Beaulieu , TD Sotnikova , S Marion , RJ Lefkowitz , RR Gainetdinov , MG Caron (2005). An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261273.

JM Beaulieu , TD Sotnikova , WD Yao , L Kockeritz , JR Woodgett , RR Gainetdinov , MG Caron (2004). Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proceedings of the National Academy of Sciences USA 101, 50995104.

ER Bennett , S Yedgar , B Lerer , RP Ebstein (1991). Phospholipase A2 activity in Epstein-Barr virus-transformed lymphoblast cells from schizophrenic patients. Biological Psychiatry 29, 10581062.

G Calabrese , M Sallese , A Stornaiuolo , E Morizio , G Palka , A De Blasi (1994). Assignment of the beta-arrestin 1 gene (ARRB1) to human chromosome 11q13. Genomics 24, 169171.

D Cotter , R Kerwin , S al-Sarraji , JP Brion , A Chadwich , S Lovestone , B Anderton , I Everall (1998). Abnormalities of Wnt signalling in schizophrenia – evidence for neurodevelopmental abnormality. Neuroreport 9, 13791383.

W Duan , Z Zhang , DM Gash , MP Mattson (1999). Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease. Annals of Neurology 46, 587597.

RP Ebstein , ER Bennett , J Hadjez , H Silver , S Yedgar , B Lerer (1990). Cyclic AMP second messenger signal generation in EBV-transformed lymphoblastoid cells from schizophrenic patients. Journal of Psychiatric Research 24, 121127.

ES Emamian , D Hall , MJ Birnbaum , M Karayiorgou , JA Gogos (2004). Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nature Genetics 36, 131137.

RR Gainetdinov , RT Premont , LM Bohn , RJ Lefkowitz , MG Caron (2004). Desensitization of G protein-coupled receptors and neuronal functions. Annual Review of Neuroscience 27, 107144.

Q Guo , W Fu , J Xie , H Luo , SF Sells , JW Geddes , V Bondada , VM Rangnekar , MP Mattson (1998). Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nature Medicine 4, 957962.

PJ Harrison , DR Weinberger (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry 10, 4068.

M Ide , T Ohnishi , M Murayama , I Matsumoto , K Yamada , Y Iwayama , I Dedova , T Toyota , T Asada , A Takashima , T Yoshikawa (2006). Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia. Journal of Neurochemistry 99, 277287.

M Ikeda , N Iwata , T Suzuki , T Kitajima , Y Yamanouchi , Y Kinoshita , T Inada , N Ozaki (2004). Association of AKT1 with schizophrenia confirmed in a Japanese population. Biological Psychiatry 56, 698700.

KE Jardemark , X Liang , V Arvanov , RY Wang (2000). Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-d-aspartate. Neuroscience 100, 19.

UG Kang , MS Seo , MS Roh , Y Kim , SC Yoon , YS Kim (2004). The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Letters 560, 115119.

C Kellendonk , EH Simpson , HJ Polan , G Malleret , S Vronskaya , V Winiger , H Moore , ER Kandel (2006). Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49, 603615.

KM Kim , KJ Valenzano , SR Robinson , WD Yao , LS Barak , MG Caron (2001). Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. Journal of Biological Chemistry 276, 3740937414.

N Kozlovsky , S Amar , RH Belmaker , G Agam (2006). Psychotropic drugs affect Ser9-phosphorylated GSK-3 beta protein levels in rodent frontal cortex. International Journal of Neuropsychopharmacology 9, 337342.

N Kozlovsky , RH Belmaker , G Agam (2000). Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. American Journal of Psychiatry 157, 831833.

N Kozlovsky , RH Belmaker , G Agam (2001). Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophrenia Research 52, 101105.

N Kozlovsky , C Shanon-Weickert , E Tomaskovic-Crook , JE Kleinman , RH Belmaker , G Agam (2004). Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. Journal of Neural Transmission 111, 15831592.

WS Lai , B Xu , KG Westphal , M Paterlini , B Olivier , P Pavlidis , M Karayiorgou , JA Gogos (2006). Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. Proceedings of the National Academy of Sciences USA 103, 1690616911.

RJ Lefkowitz , SK Shenoy (2005). Transduction of receptor signals by beta-arrestins. Science 308, 512517.

CM Lewis , DF Levinson , LH Wise , LE DeLisi , RE Straub , I Hovatta , NM Williams , SG Schwab , AE Pulver , SV Faraone , (2003). Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. American Journal of Human Genetics 73, 3448.

M Li , X Wang , MK Meintzer , T Laessig , MJ Birnbaum , KA Heidenreich (2000). Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Molecular Cell Biology 20, 93569363.

X Li , KM Rosborough , AB Friedman , W Zhu , KA Roth (2007). Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. International Journal of Neuropsychopharmacology 10, 719.

A Matuzany-Ruban , S Avissar , G Schreiber (2005). Dynamics of beta-arrestin1 protein and mRNA levels elevation by antidepressants in mononuclear leukocytes of patients with depression. Journal of Affective Disorders 88, 307312.

C Nadri , B Dean , E Scarr , G Agam (2004). GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. Schizophrenia Research 71, 377382.

RH Oakley , SA Laporte , JA Holt , LS Barak , MG Caron (2001). Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis. Journal of Biological Chemistry 276, 1945219460.

J Papkoff , M Aikawa (1998). WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. Biochemical & Biophysical Research Communications 247, 851858.

SK Park , MD Nguyen , A Fischer , MP Luke , B Affar el , PB Dieffenbach , HC Tseng , Y Shi , LH Tsai (2005). Par-4 links dopamine signaling and depression. Cell 122, 275287.

T Paunio , A Tuulio-Henriksson , T Hiekkalinna , M Perola , T Varilo , T Partonen , TD Cannon , J Lonnqvist , L Peltonen (2004). Search for cognitive trait components of schizophrenia reveals a locus for verbal learning and memory on 4q and for visual working memory on 2q. Human Molecular Genetics 13, 16931702.

C Scassellati , C Bonvicini , J Perez , L Bocchio-Chiavetto , GB Tura , G Rossi , G Racagni , M Gennarelli (2004). Association study of -1727 A/T, -50 C/T and (CAA)n repeat GSK-3beta gene polymorphisms with schizophrenia. Neuropsychobiology 50, 1620.

SG Schwab , B Hoefgen , C Hanses , MB Hassenbach , M Albus , B Lerer , M Trixler , W Maier , DB Wildenauer (2005). Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. Biological Psychiatry 58, 446450.

P Seeman , S Kapur (2000). Schizophrenia: more dopamine, more D2 receptors. Proceedings of the National Academy of Sciences USA 97, 76737675.

G Shaltiel , A Shamir , L Nemanov , Y Yaroslavsky , B Nemets , RP Ebstein , RH Belmaker , G Agam (2001). Inositol monophosphatase activity in brain and lymphocyte-derived cell lines of bipolar patients. World Journal of Biological Psychiatry 2, 9598.

J Shapiro , RH Belmaker , A Biegon , A Seker , G Agam (2000). Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients. Journal of Neural Transmission 107, 603607.

W Stefansky (1972). Rejecting outliers in factorial designs. Technometrics 14, 469479.

P Svenningsson , ET Tzavara , R Carruthers , I Rachleff , S Wattler , M Nehls , DL McKinzie , AA Fienberg , GG Nomikos , P Greengard (2003). Diverse psychotomimetics act through a common signaling pathway. Science 302, 14121415.

A Szczepankiewicz , M Skibinska , J Hauser , A Slopien , A Leszczynska-Rodziewicz , P Kapelski , M Dmitrzak-Weglarz , PM Czerski , JK Rybakowski (2006). Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. Neuropsychobiology 53, 5156.

Z Zhao , H Ksiezak-Reding , S Riggio , V Haroutunian , GM Pasinetti (2006). Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophrenia Research 84, 114.

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  • ISSN: 1461-1457
  • EISSN: 1469-5111
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