Cyclic Nucleotide Phosphodiesterases: Gene Complexity, Regulation by Phosphorylation, and Physiological Implications

Abstract

Publisher Summary The intracellular levels of cyclic nucleotides are regulated through synthesis by adenylyl and guanylyl cyclases and also degradation by phosphodiesterases (PDEs). In many cases, PDEs have been shown, or at least implicated, to be important not only in maintaining a steady-state level of cAMP and cGMP, but also in modulating rapid oscillation of intracellular cyclic nucleotide level in response to extracellular stimuli. This chapter reports regulation of cellular PDE activity via phosphorylation–dephosphorylation reactions. The chapter presents speculation on the physiological significance that phosphorylation may play in the modulation of cyclic nucleotide levels and on the possible effect of this mode of regulation on cellular function. The discussion includes detailed information about regulation of PDE1, PDE2, PDE3, PDE4, PDE5 activities. With the recent advances in molecular cloning of the PDEs, it has become apparent that many isoforms exist within single gene families and that these isoforms have different functions depending on tissue distribution and cellular localization. Determining the role—that phosphorylation plays in regulating specific PDE isoforms in specific tissues and cell types—can enable researchers to gain insight into the control of cyclic nucleotide signaling processes. The complexity of PDEs also poses significant challenges to future pharmacological studies on PDEs in terms of drug specificity.