Glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly abundant in brain is a negative regulator of signal transduction cascades including the phosphatidylinositol-3-kinase (PI3-K)/Akt and the Wnt. GSK-3beta has recently been suggested to be an intracellular target of the mood stabilizers lithium and valproate and of the typical and atypical antipsychotic agents haloperidol and clozapine. We have previously shown that these agents do not alter frontal cortex GSK-3beta protein levels or activity. The current study was conducted to assess the effect of psychotropic drugs on phospho-Ser9-GSK-3beta levels in rodents. Chronic administration of haloperidol to rats resulted in a significant reduction in frontal cortex phospho-Ser9-GSK-3beta protein levels and no change in those of GSK-3alpha, while chronic administration of clozapine or subchronic administration of valproate caused significant elevation of GSK-3beta protein levels. Mice treated chronically with lithium exhibited the most prominent elevation in phospho-Ser9-GSK-3beta. The results support the notion that GSK-3beta may be a common target for mood stabilizers and neuroleptics.
Background: Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders.
Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, beta-arrestin1, AKT1 and GSK-3beta 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. beta-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-3beta protein levels in schizophrenia but not in those of AKT1, Par-4 or beta-arrestin1. Elevated beta-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3beta 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 beta-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3beta 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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