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DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling

Millar, J. Kirsty and Pickard, Benjamin S. and Mackie, Shaun and James, Rachel and Christie, Sheila and Buchanan, Sebastienne R. and Malloy, M. Pat and Chubb, Jennifer E. and Huston, Elaine and Baillie, George S. and Thomson, Pippa A. and Hill, Elaine V. and Brandon, Nicholas J. and Rain, Jean-Christophe and Camargo, L. Miguel and Whiting, Paul J. and Houslay, Miles D. and Blackwood, Douglas H. R. and Muir, Walter J. and Porteous, David J. (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science, 310 (5751). pp. 1187-1191. ISSN 1095-9203

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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.