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DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling
Abstract
The disrupted in schizophrenia 1 ( DISC1 ) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B ( PDE4B ) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3′,5′-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
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In the citing paper
“For example, disrupted in schizophrenia 1 (DISC1) normally provides negative feedback on cAMP signalling, but a mutation in DISC1 decreased the activity of the phosphodiesterase PDE4B in the presence of high concentrations of cAMP128.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [128]
In the citing paper
“Particularly relevant to stress signaling in PFC, DISC1 anchors the phosphodiesterases (PDE4s) that catabolize cAMP and regulate its signaling121,125.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [121]
In the citing paper
“Emerging data indicate that the scaffolding protein Disrupted In Schizophrenia 1 (DISC1) is critical for regulation of the stress response in PFC, suggesting that genetic insults that interfere with the function of this protein increase the risk for stress-related psychiatric disorders.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [121]
In the citing paper
“Mutations in DISC1 are associated with high rates of mental illness120,121, and more subtle polymorphisms are associated with decreased PFC gray matter and impaired working memory122,123.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [121]
Citations
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Self-citationThe cyclic AMP system andDrosophila learning
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Stress signalling pathways that impair prefrontal cortex structure and function
Arnsten, A. F. T. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2648 · Cited by 3,299
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Self-citationConti, M., & Beavo, J. A. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.060305.150444 · Cited by 1,219
Metadata
- Authors
- Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., Malloy, M. P., Chubb, J. E., Huston, E., Baillie, G. S., Thomson, P. A., Hill, E. V., Brandon, N. J., Rain, J.-C., Camargo, L. M., Whiting, P. J., Houslay, M. D., Blackwood, D. H. R., Muir, W. J., & Porteous, D. J.
- Affiliations
- Royal Edinburgh Hospital (GB)
- Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK.
- Corresponding author
- Millar, J. Kirsty
- ORCID
- Venue
- Science
- Published
- 2005-11-18
- Volume
- 310
- Issue
- 5751
- Pages
- 1187-1191
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2105051672
- Cited by
- 648
- References
- 20
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 12 · 2023: 11 · 2022: 14 · 2021: 13 · 2020: 14 · 2019: 19 · 2018: 21 · 2017: 24 · 2016: 28 · 2015: 47 · 2014: 39 · 2013: 24 · 2012: 35
- FWCI
- 20.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- DISC1, PDE4B, schizophrenia, cAMP signaling, phosphodiesterase 4, balanced translocation, protein-protein interaction, second messengers, genetic susceptibility, chronic mental illness
- MeSH terms
- Cyclic AMP, Adult, Affective Disorders, Psychotic, Animals, Cell Line, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 16, Enzyme Activation, Humans, Male, Nerve Tissue Proteins, Protein Binding, Schizophrenia, Translocation, Genetic, 3',5'-Cyclic-AMP Phosphodiesterases, Signal Transduction, Cadherins, Genetic Predisposition to Disease, Rats, Cyclic Nucleotide Phosphodiesterases, Type 4
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