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| http://purl.uniprot.org/citations/21376063 | http://www.w3.org/2000/01/rdf-schema#comment | "Disrupted-In-Schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.neuropharm.2011.02.020"xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/author | "Liu F."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/author | "Wang M."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/author | "Lipina T.V."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/author | "Roder J.C."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/date | "2012"xsd:gYear |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/name | "Neuropharmacology"xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/pages | "1252-1262"xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/title | "Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice."xsd:string |
| http://purl.uniprot.org/citations/21376063 | http://purl.uniprot.org/core/volume | "62"xsd:string |
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