Cited by 652Phosphodiesterase function and regulationSchizophrenia research and treatmentProtein Tyrosine Phosphatases

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DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling

Millar, J. Kirsty, Pickard, Benjamin S., Mackie, Shaun, James, Rachel, Christie, Sheila, Buchanan, Sebastienne R., Malloy, M. Pat, Chubb, Jennifer E., Huston, Elaine, Baillie, George S., Thomson, Pippa A., Hill, Elaine V., Brandon, Nicholas J., Rain, Jean-Christophe, Camargo, L. Miguel, Whiting, Paul J., Houslay, Miles D., Blackwood, Douglas H. R., Muir, Walter J., Porteous, David J.·2005·Science

DOI 10.1126/science.1112915

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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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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: James, Rachel
Baillie, George S.
Thomson, Pippa A.
Brandon, Nicholas J.
Rain, Jean-Christophe
Camargo, L. Miguel
Whiting, Paul J.
Houslay, Miles D.
Blackwood, Douglas H. R.
Porteous, David J.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2005-11-18
Volume: 310
Issue: 5751
Pages: 1187-1191
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1112915
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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DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling

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