The PDE4 family of cAMP-degrading enzymes has been the focus of extensive research due to the wide range of pathological conditions and disease states that could potentially benefit from treatment with PDE4 inhibitors. Significant advances have recently been made in the understanding of PDE4 biology and the role it plays in specific signaling systems, however, this has only served to highlight the complexity of the involvement of PDE4 isoforms in signaling mechanisms and so has emphasized that much more remains to be uncovered. A number of proteins that bind to PDE4 have been identified and their interactions partially characterized, but undoubtedly a myriad of interacting partners still await discovery before we can even begin to understand their functions. It is clear, however, that PDE4 enzymes are fundamental to the compartmentalization of cAMP signaling and are involved in both the spatial and temporal regulation of signal dissemination. It is also becoming increasingly clear that they are positioned to integrate crosstalk with other major signaling pathways such as the ERK MAP kinase pathway, which controls many critical cellular functions. The PDE4 family comprises some 20 distinct isoforms with it being entirely possible that the list of known PDE4 isoforms is incomplete. The isoforms identified to date have been very highly conserved between species, despite evolutionary pressure, suggesting that they will all transpire to have important functions with minimal redundancy. It is possible that the same isoform will perform different functions in different cell types dependent on the cell-specific expression of binding partners. In fact, the observed cell-specific action of certain inhibitors is likely a consequence of the availability of different interacting species that all serve to influence PDE4 localization, conformation and regulation. It will therefore be of increasing importance to the development of therapeutic inhibitors that PDE4 isoforms and their binding partners are studied in the appropriate cells or tissues that will act as targets for therapeutics, for example, cells of the CNS or inflammatory cells. Increased knowledge of the protein-protein interactions of PDE4 and the processes they regulate will be facilitated by techniques such as peptide array, dominant negative displacement and RNA silencing. This enhanced understanding will aid in the design of increasingly specific PDE4 inhibitors, which target unique isoforms by virtue of their protein-protein interactions. Hopefully, isoform-specific PDE4 inhibitors will eliminate the prohibitive side effects seen with current universal PDE4 inhibitors and thereby allow PDE4 inhibitors to fulfill their promise as therapeutic agents.

Acknowledgements This work was supported by grants from the Medical Research Council (UK) (G8604010; 0600765), the Leducq Foundation (Paris) and by the European Union (037189).

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