Introduction
Cyclic adenosine 3’5’-monophosphate (cAMP) and cyclic guanosine 3’5’-monophoshpate
(cGMP) are critical intracellular second-messengers involved in the transduction of
a wide variety of extracellular stimuli, including peptide hormones, growth factors,
cytokines, neurotransmitters and light. These messengers modulate many fundamental
biological processes, including growth, differentiation, apoptosis, glycogenolysis,
lipolysis, immune/inflammatory responses, etc.
By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases (PDEs)
are important determinants in regulating the intracellular concentrations and, consequently,
the biological actions of these second-messengers (Fig. 1). The advent of molecular
genetics has revealed the extraordinary complexity and diversity of the mammalian
PDE superfamily, which contains at least 10 highly regulated and structurally-related
gene families (PDEs 1-10).1-8 As depicted in Figure 1, some PDEs are highly specific for hydrolysis of cAMP (PDEs
4,7,8), some are cGMP-specific (PDEs 5,6,9), and some exhibit mixed specificity (PDEs
1,2,3,10). Most gene families are comprised of more than one isogene (indicated by
A-D in Table 1). At least 19 genes encoding more than 30 isoforms have been identified.
PDE families differ with respect to their primary structures, sensitivity to specific
inhibitors, tissue distribution, subcellular localization, and mechanisms of regulation
(Table 1).2-6 Within individual families, different mRNAs are generated from the same gene by use
of different transcription initiation sites or by alternative mRNA splicing. These
variant PDE isoforms are often tissue-specific and selectively expressed in various
tissues and cell types.2-6 The importance of cyclic nucleotide signaling in cell regulation and the molecular
diversity of PDEs has presented targets for selective interventions and development
of family-specific PDE inhibitors as therapeutic agents. This brief review will discuss
some general characteristics of PDEs and then focus on the cellular biology and diverse
functions of different PDE isoforms and their potential as therapeutic targets.
