title: 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.
authors.affiliation: Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. Kirsty.Millar@ed.ac.uk
authors.forename: J Kirsty
authors.initials: JK
authors.lastname: Millar
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Pickard
authors.forename: Shaun
authors.initials: S
authors.lastname: Mackie
authors.forename: Rachel
authors.initials: R
authors.lastname: James
authors.forename: Sheila
authors.initials: S
authors.lastname: Christie
authors.forename: Sebastienne R
authors.initials: SR
authors.lastname: Buchanan
authors.forename: M Pat
authors.initials: MP
authors.lastname: Malloy
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Chubb
authors.forename: Elaine
authors.initials: E
authors.lastname: Huston
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Pippa A
authors.initials: PA
authors.lastname: Thomson
authors.forename: Elaine V
authors.initials: EV
authors.lastname: Hill
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rain
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Camargo
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Whiting
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Muir
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000341:Affective Disorders, Psychotic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics; D002460:Cell Line; D002878:Chromosomes, Human, Pair 1; D002885:Chromosomes, Human, Pair 16; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014178:Translocation, Genetic
chemical_list: C112316:CDH8 protein, human; D015820:Cadherins; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human