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 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.
Millar
J Kirsty
JK
Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, UK. Kirsty.Millar@ed.ac.uk
Pickard
Benjamin S
BS
Mackie
Shaun
S
James
Rachel
R
Christie
Sheila
S
Buchanan
Sebastienne R
SR
Malloy
M Pat
MP
Chubb
Jennifer E
JE
Huston
Elaine
E
Baillie
George S
GS
Thomson
Pippa A
PA
Hill
Elaine V
EV
Brandon
Nicholas J
NJ
Rain
Jean-Christophe
JC
Camargo
L Miguel
LM
Whiting
Paul J
PJ
Houslay
Miles D
MD
Blackwood
Douglas H R
DH
Muir
Walter J
WJ
Porteous
David J
DJ
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
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