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Science 310 (5751): 1187-1191

Copyright © 2005 by the American Association for the Advancement of Science

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

J. Kirsty Millar,1*{dagger} Benjamin S. Pickard,1* Shaun Mackie,1 Rachel James,1 Sheila Christie,1 Sebastienne R. Buchanan,1 M. Pat Malloy,1 Jennifer E. Chubb,1 Elaine Huston,2 George S. Baillie,2 Pippa A. Thomson,1 Elaine V. Hill,2 Nicholas J. Brandon,3 Jean-Christophe Rain,4 L. Miguel Camargo,3 Paul J. Whiting,3 Miles D. Houslay,2 Douglas H. R. Blackwood,1,5 Walter J. Muir,1,5 David J. Porteous1

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.

1 Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK.
2 Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, UK.
3 The Neuroscience Research Centre, Merck Sharp and Dohme, Ltd. (MSD), Terlings Park, Harlow, Essex, CM20 2QR, UK.
4 Hybrigenics S.A., 3-5 Impasse Reille–75014 Paris, France.
5 Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: Kirsty.Millar{at}ed.ac.uk


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