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

Abstract

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.