RGD Reference Report - Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. - Rat Genome Database

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Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3.

Authors: Sutton, LP  Honardoust, D  Mouyal, J  Rajakumar, N  Rushlow, WJ 
Citation: Sutton LP, etal., J Neurochem. 2007 Jul;102(1):153-69. Epub 2007 May 1.
RGD ID: 2311569
Pubmed: PMID:17472703   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2007.04527.x   (Journal Full-text)

Protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and members of the Wnt signal transduction pathway were recently found to be altered in schizophrenia and targeted by antipsychotic drugs. In the current study, selected Wnt signalling proteins were investigated to determine if they are altered by the antipsychotics clozapine or haloperidol in the rat prefrontal cortex. Pheochromocytoma (PC12) and neuroblastoma (SH-SY5Y) cells were also used to elucidate how antipsychotics generated the pattern of changes observed in vivo. Western blotting (WB) revealed that treatment with haloperidol or clozapine caused an up-regulation of Wnt-5a, dishevelled-3, Axin, total and phosphorylated GSK-3 and beta-catenin protein levels. Treatment of PC12 and SH-SY5Y cells with a variety of pharmacological agents as well as the over-expression of several Wnt related proteins failed to mimic the pattern observed in vivo following antipsychotic treatment. However, the over-expression of dishevelled-3 nearly perfectly duplicated the changes observed in vivo. Immunoprecipitations (IP) conducted using protein isolated from the rat prefrontal cortex indicated that dishevelled-3 is associated with the D2 dopamine receptor thereby suggesting that antipsychotics may act on dishevelled-3 via D2 dopamine receptors to initiate a cascade of downstream changes involving Axin, GSK-3 and beta-catenin that may help to alleviate psychosis in schizophrenic patients.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to xenobiotic stimulus  IEP 2311569clozapine and haloperidolRGD 
Wnt signaling pathway  IDA 2311569 RGD 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Drd2  (dopamine receptor D2)
Dvl3  (dishevelled segment polarity protein 3)


Additional Information