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Co-ordinated action of DISC1, PDE4B and GSK3β in modulation of cAMP signalling

Molecular Psychiatry volume 16, pages 693–694 (2011)Cite this article

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Disrupted-in-Schizophrenia-1 (DISC1) is a risk factor for major mental illness, including schizophrenia and depression.1 DISC1 interacts with multiple proteins involved in intracellular signalling pathways, including two enzymes cAMP phosphodiesterase-4 (PDE4)2 and glycogen synthase kinase-3β (GSK3β),3 that are inhibited by the prototypic antidepressant/antipsychotic Rolipram4 and the mood stabiliser Lithium (LiCl),5 respectively. PDE4 itself has been directly implicated as a risk factor for mental illness,1, 2, 6 whereas the likely involvement of GSK3β in molecular pathways underlying mental illness is long standing and now linked to DISC1.7 DISC1 inhibits GSK3β,3 and we have previously suggested that DISC1 similarly modulates PDE4.2 These enzymes have overlapping binding sites on DISC1,3, 8 suggesting that their function within the DISC1 complex may be related. Moreover, it has recently been demonstrated that GSK3β phosphorylates PDE4D.9 Accordingly, we now provide evidence that pharmacological inhibition of GSK3β decreases PDE4 activity, and demonstrate that the stimulatory effect of Forskolin upon PDE4 activity is modulated by the co-ordinated action of DISC1 and GSK3β.

To assess the potential effects of DISC1 overexpression on PDE4 activity, a stably transfected SH-SY5Y cell line was created, which inducibly overexpresses full-length wild-type human DISC1 (fl-DISC, Supplementary Figure S1a). At basal cAMP levels, DISC1 overexpression does not, by itself, influence PDE4 activity (Bradshaw et al., in preparation), but it does increase the magnitude of the PDE4 inhibitory response to LiCl (Figure 1c). PDE4 activity was reduced by 26.2% (±3.5) in response to 10 mM LiCl in cells overexpressing fl-DISC1, in contrast to the 16% (±1.7) reduction in activity observed in control cells (P=0.05). Thus, in SH-SH5Y cells, overexpression of fl-DISC1 enhances the effect of pharmacological inhibition of GSK3β.

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Acknowledgements

This work was supported by a University of Edinburgh PhD Fellowship to BC, a Sidney Bear/NARSAD Distinguished Investigator Award to DJP, MRC support to DJP and JKM (G0600214) and an RCUK Fellowship to JKM.

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Author notes

  1. J K Millar and D J Porteous: These authors contributed equally to this work.

Authors and Affiliations

  1. The Centre for Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, UK

    B C Carlyle, S Mackie, S Christie, J K Millar & D J Porteous

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    B C Carlyle

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  1. B C Carlyle
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  2. S Mackie
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  3. S Christie
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  4. J K Millar
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  5. D J Porteous
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Correspondence to B C Carlyle.

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Carlyle, B., Mackie, S., Christie, S. et al. Co-ordinated action of DISC1, PDE4B and GSK3β in modulation of cAMP signalling. Mol Psychiatry 16, 693–694 (2011). https://doi.org/10.1038/mp.2011.17

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