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

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.