PDE4 cAMP-specific phosphodiesterases

• Published in: Progress in Nucleic Acid Research and Molecular Biology Vol. 69; pp. 249 - 315
• Main Author: Houslay, Miles D
• Format: Book Chapter Journal Article
• Language: English
• Published: United States Elsevier Science & Technology 2001
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - genetics; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Amino Acid Sequence; Animals; Biochemistry; Catalytic Domain; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4; Genetics (non-medical); Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Mice; Mice, Knockout; Models, Molecular; Molecular biology; Molecular Sequence Data; Phosphorylation; Protein Conformation; Protein Structure, Tertiary; Rats; PDE; UCR; EGF; PDE4; LR; PKA; TSH; cGMP; FSH; cAMP
• ISBN: 9780125400695; 0125400691
• ISSN: 0079-6603
• DOI: 10.1016/S0079-6603(01)69049-4

This chapter discusses the cyclic nucleotide phosphodiesterases (PDE4) cyclic Adenosine monophosphate (cAMP)-specific phosphodiesterases. Inhibitors selective for PDE4 enzymes have proved to be extremely informative in identifying the key role that this enzyme activity plays in regulating a variety of important processes related to the inflammatory processes, cell survival, memory, and learning. Molecular biological studies have proved to be crucial in delineating the diversity of this enzyme family. The fact that this diversity has been sustained during evolution, and that particular PDE4 isoenzymes are selectively expressed in different cells, suggests that the various PDE4 isoforms have distinct roles in regulating particular cellular processes. PDE4B, 4C, and 4D isoenzymes are regulated by growth stimulatory responses mediated as a consequence of extracellular-signal-regulated kinases (ERK) activation. In contrast to this, the commonly expressed PDE4A4/5 long form can be regulated through PI-3 kinase-dependent processes and provides a unique target for caspase-3 action, implying a role in cell survival. Indeed, the fact that caspase-3 activation serves to disrupt the intracellular targeting of this enzyme may serve as a paradigm for a means of altering/ablating the role of a PDE4 enzyme, by removing it from a functionally relevant compartment. In this way, new generations of isoenzyme selective inhibitors might be attained.