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

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

Research output: Contribution to journalArticle

513 Citations (Scopus)

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.
LanguageEnglish
Pages1187-1191
Number of pages5
JournalScience
Volume310
Issue number5751
DOIs
Publication statusPublished - 18 Nov 2005

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Type 4 Cyclic Nucleotide Phosphodiesterase
Schizophrenia
Second Messenger Systems
Adenosine
Genes
Psychiatry
Chronic Disease
Learning

Keywords

  • 3',5'-cyclic-AMP phosphodiesterases
  • genetic disorders
  • signal transduction translocation
  • enzymology
  • schizophrenia
  • adult affective disorders

Cite this

Millar, J. K., Pickard, B. S., Mackie, S., James, R., Christie, S., Buchanan, S. R., ... Porteous, D. J. (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science, 310(5751), 1187-1191. https://doi.org/10.1126/science.1112915
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. ; Blackwood, Douglas H. R. ; Muir, Walter J. ; Porteous, David J. / DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. In: Science. 2005 ; Vol. 310, No. 5751. pp. 1187-1191.
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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.",
keywords = "3',5'-cyclic-AMP phosphodiesterases, genetic disorders, signal transduction translocation, enzymology, schizophrenia , adult affective disorders",
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Millar, JK, Pickard, BS, Mackie, S, James, R, Christie, S, Buchanan, SR, Malloy, MP, Chubb, JE, Huston, E, Baillie, GS, Thomson, PA, Hill, EV, Brandon, NJ, Rain, J-C, Camargo, LM, Whiting, PJ, Houslay, MD, Blackwood, DHR, Muir, WJ & Porteous, DJ 2005, 'DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling' Science, vol. 310, no. 5751, pp. 1187-1191. https://doi.org/10.1126/science.1112915

DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. / 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.; Blackwood, Douglas H. R.; Muir, Walter J.; Porteous, David J.

In: Science, Vol. 310, No. 5751, 18.11.2005, p. 1187-1191.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling

AU - Millar, J. Kirsty

AU - Pickard, Benjamin S.

AU - Mackie, Shaun

AU - James, Rachel

AU - Christie, Sheila

AU - Buchanan, Sebastienne R.

AU - Malloy, M. Pat

AU - Chubb, Jennifer E.

AU - Huston, Elaine

AU - Baillie, George S.

AU - Thomson, Pippa A.

AU - Hill, Elaine V.

AU - Brandon, Nicholas J.

AU - Rain, Jean-Christophe

AU - Camargo, L. Miguel

AU - Whiting, Paul J.

AU - Houslay, Miles D.

AU - Blackwood, Douglas H. R.

AU - Muir, Walter J.

AU - Porteous, David J.

PY - 2005/11/18

Y1 - 2005/11/18

N2 - 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.

AB - 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.

KW - 3',5'-cyclic-AMP phosphodiesterases

KW - genetic disorders

KW - signal transduction translocation

KW - enzymology

KW - schizophrenia

KW - adult affective disorders

UR - http://www.ncbi.nlm.nih.gov/pubmed/16293762

U2 - 10.1126/science.1112915

DO - 10.1126/science.1112915

M3 - Article

VL - 310

SP - 1187

EP - 1191

JO - Science

T2 - Science

JF - Science

SN - 0036-8075

IS - 5751

ER -