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

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 schizophr...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2005-11, Vol.310 (5751), p.1187-1191
Main Authors: 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., Douglas H. R. Blackwood, Muir, Walter J., Porteous, David J.
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - genetics
3',5'-Cyclic-AMP Phosphodiesterases - metabolism
Adult
Adult and adolescent clinical studies
Affective Disorders, Psychotic - genetics
Affective Disorders, Psychotic - metabolism
Anatomy
Animals
Antibodies
Biological and medical sciences
Bipolar disorder
Cadherins - genetics
Cell Line
Cell lines
Cellular immunity
Chromosome abnormalities
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 16
Comparative analysis
Cyclic AMP - metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4
Enzyme Activation
Fractions
Genetic Predisposition to Disease
Genetics
HEK293 cells
Humans
Male
Medical research
Medical sciences
Memory
Mental Disorders
Mood disorders
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons
Protein Binding
Protein isoforms
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Psychoses
Rats
Schizophrenia
Schizophrenia - enzymology
Schizophrenia - genetics
Schizophrenia - metabolism
Signal Transduction
Translocation, Genetic
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1112915