PDE4 Associates with Different Scaffolding Proteins Modulating Interactions as Treatment for Certain Diseases

A.C. McCahill, E. Huston, X. Li, and M.D. Houslay(*)

Contents

1 Introduction 126

2 PDE4 128

2.1 Structure of PDE4 129

2.2 Regulation of PDE4 130

2.3 Therapeutic Uses and Limitations of PDE4 Inhibitors 133

2.4 Targeting/Compartmentalization of PDE4 135

2.5 Intracellular Targeting via Protein-Protein Interactions 137

3 Alternatives to PDE4 Catalytic Site Inhibitors 150

3.1 Peptide Array Analyses to Identify Protein-Protein Interaction Sites 151

3.2 Disruptor Therapeutics 153

3.3 Dominant Negative Approach to Inhibition by Displacement 153

4 Conclusions 155

References 156

Abstract cAMP is an ubiquitous second messenger that is crucial to many cellular processes. The sole means of terminating the cAMP signal is degradation by cAMP phosphodiesterases (PDEs). The PDE4 family is of particular interest because PDE4 inhibitors have therapeutic potential for the treatment of various inflammatory and auto-immune diseases and also have anti-depressant and memory-enhancing effects. The subcellular targeting of PDE4 isoforms is fundamental to the compart-mentalization of cAMP signaling pathways and is largely achieved via proteinprotein interactions. Increased knowledge of these protein-protein interactions and their regulatory properties could aid in the design of novel isoform-specific inhibitors with improved efficacy and fewer prohibitive side effects.

M.D. Houslay

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G128QQ, Scotland, UK [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

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