The International Journal of Neuropsychopharmacology

Research Article

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

Shirly Amara1, Galit Shaltiela1, Liad Manna1, Alon Shamira1, Brian Deana2, Elizabeth Scarra2, Yuly Bersudskya1, R. H. Belmakera1 and Galila Agama1 c1

a1 Stanley Research Center, Faculty of Health Science, Ben-Gurion University of the Negev, and Mental Health Center, Beer-Sheva, Israel

a2 The Rebecca L. Cooper Research Laboratories at the Mental Health Research Institute of Victoria, Australia


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.

(Received April 12 2007)

(Reviewed May 21 2007)

(Revised May 27 2007)

(Accepted June 12 2007)

(Online publication August 06 2007)


c1 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.: +972-8-6401737 Fax: +972-8-6401740 E-mail: