Research: Schizophrenia - cAMP interactions

18 November 2005

The identification of a candidate susceptibility gene for schizophrenia provides insight into molecular mechanisms that may underlie the disease.

The new susceptibility gene, phosphodiesterase 4B (PDE4B) was identified by Professor David Porteous (University of Edinburgh) and colleagues through studies of a chromosome abnormality found in an individual with schizophrenia. The gene is particularly interesting as PDE4B inactivates cyclic AMP (cAMP) – a messenger molecule involved in learning, memory and mood.

Even more intriguingly, the researchers showed that PDE4B interacts with the protein produced by the disrupted in schizophrenia 1 (DISC1) gene, one of the most promising candidate genes for schizophrenia. This interaction is influenced by levels of cAMP: increased levels of cAMP in the cell lead to the phosphorylation and activation of PDE4B (by protein kinase A), which then dissociates from DISC1, ready to inactivate cAMP.

Schizophrenia and bipolar affective disorder are increasingly thought to be closely related. This new research suggests a mechanistic link, particularly given that mice lacking an equivalent gene behave as if they are taking antidepressants, and the antidepressant Rolipram is a selective inhibitor of PDE4. If cAMP signalling is a unifying link between schizophrenia and bipolar affective disorder, as the researchers suggest, drugs that tweak the balance of the PDE4B–DISC1 interaction could become important new therapies for these disorders.

External links

• Millar JK et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005;310(5751):1187–91.