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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:
  • Published online: 06 August 2007

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.

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:
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