Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia.
Int J Neuropsychopharmacol
; 11(2): 197-205, 2008 Mar.
Article
em En
| MEDLINE
| ID: mdl-17681085
ABSTRACT
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Transtorno Bipolar
/
Linfócitos
/
Transdução de Sinais
/
Córtex Cerebral
/
Receptores de Dopamina D2
Tipo de estudo:
Clinical_trials
/
Observational_studies
País/Região como assunto:
Asia
/
Oceania
Idioma:
En
Revista:
Int J Neuropsychopharmacol
Assunto da revista:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Israel