Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Тодорова, Валентина; Elbein, Alan D.; Kyosseva, Svetlana V.

doi:10.1038/sj.npp.1300211

Cited by 16 publications

(11 citation statements)

References 70 publications

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“…These results suggest relative uncoupling of GPCRs from their ability to propagate intracellular signals in schizophrenia. These data add to the literature of alterations in regulatory and downstream signaling pathways in this illness (Baracskay et al, 2006; Clinton et al, 2005; Emamian et al, 2004; Kyosseva, 2004a, b; Kyosseva et al, 1999; Manji et al, 2003; Todorova et al, 2003; Yuan et al, 2010). …”

Section: 1 Discussionsupporting

confidence: 66%

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Funk

Haroutunian

Meador‐Woodruff

et al. 2014

Schizophrenia Research

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Background Current pharmacological treatments for schizophrenia target G protein-coupled receptors (GPCRs), including dopamine receptors. Ligand bound GPCRs are regulated by a family of G protein-coupled receptor kinases (GRKs), members of which uncouple the receptor from heterotrimeric G proteins, desensitize the receptor, and induce receptor internalization via the arrestin family of scaffolding and signaling molecules. GRKs initiate the activation of downstream signaling pathways, can regulate receptors and signaling molecules independent of GPCR phosphorylation, and modulate epigenetic regulators like histone deacetylases (HDACs). We hypothesize that expression of GRK proteins are altered in schizophrenia, consistent with previous findings of alterations up and downstream from this family of molecules that facilitate intracellular signaling processes. Methods In this study we measured protein expression via Western blot analysis for GRKs 2, 3, 5, and 6 in the anterior cingulate cortex of patients with schizophrenia (N = 36) and a comparison group (N = 33). To control for antipsychotic treatment we measured these same targets in haloperidol treated vs. untreated rats (N = 10 for both). Results We found increased levels of GRK5 in schizophrenia. No changes were detected in GRK protein expression in rats treated with haloperidol decanoate for 9 months. Conclusion These data suggest that increased GRK5 expression may contribute the the pathophysiology of schizophrenia via abnormal regulation of the cytoskeleton, endocytosis, signaling, GPCRs, and histone modification.

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Section: 1 Discussionsupporting

confidence: 66%

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Funk

Haroutunian

Meador‐Woodruff

et al. 2014

Schizophrenia Research

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“…Emphasizing the importance of BRD1 as a cardinal transcriptional regulator, we demonstrate widespread expression alterations in the brains of Brd1 +/mice. This includes altered expression of transcriptional regulators and immediate early genes (IEGs) like Homer, Bdnf, c-fos, c-jun, and Shank which have previously been linked to the etiopathology of mental disorders (62)(63)(64). We further find that the identified DEGs are enriched for schizophrenia risk and that they cluster within known GWAS schizophrenia risk loci.…”

Section: Enrichment Of Schizophrenia Riskmentioning

confidence: 68%

The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice

Qvist

Christensen

Vardya³

et al. 2017

Biological Psychiatry

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“…Previous studies of the MAPK-associated pathway found changes in several constituent proteins. For example, both protein and transcript levels of ERK2, c-fos, and c-Jun were increased in the thalamus, whereas c-Jun protein and Elk-1, CREB, and ATF-2 protein levels and transcripts were noted to be increased in the cerebellar vermis (Kyosseva, 2004a;Kyosseva et al, 2000;Todorova et al, 2003). Other proteins of the MAPK pathway including MEK1, MEK2, RSK1, B-Raf, and CREB were decreased in the frontal cortex (Yuan et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

Funk

McCullumsmith

Haroutunian

et al. 2011

Neuropsychopharmacol

133

102

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Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3 0 -5 0 -cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK-and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC ¼ 36, DLPFC ¼ 35) and a comparison (ACC ¼ 33, DLPFC ¼ 31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK-and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK-and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK-and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.

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Increased Expression of c-Jun Transcription Factor in Cerebellar Vermis of Patients with Schizophrenia

Cited by 16 publications

References 70 publications

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia

The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice

Abnormal Activity of the MAPK- and cAMP-Associated Signaling Pathways in Frontal Cortical Areas in Postmortem Brain in Schizophrenia

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