Associate editor: V. Schini-KerthCyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents
Introduction
Today, although academic and pharmaceutical research has clearly characterized the gene or receptor implicated in numerous pathologies, a great number of diseases remain unresolved, inasmuch as they have multifactorial origins. Since 1990, with the discovery of many and various receptor families, disregarding intracellular signaling, basic research has extensively developed new efficient therapeutic compounds by SAR and graphic computer-aided receptor mapping (Hibert et al., 1988, Hibert et al., 1991). Downstream of receptor regulation, intracellular signaling plays a major role by governing normal and pathological cell responses. Alterations in intracellular signaling may be 1 clue toward addressing unresolved diseases. Adenosine 3′, 5′-cyclic monophosphate (cAMP) and guanosine 3′, 5′-cyclic monophosphate (cGMP) are ubiquitous nucleotides that have been described as the first second messengers (Sutherland & Rall, 1958, Ashman et al., 1963). In concert with intracellular calcium and IP3, they orchestrate intracellular signaling.
Downstream of cyclic nucleotide synthesis by adenylyl and guanylyl cyclases, the multigenic family of cyclic nucleotide phosphodiesterases (PDEs, EC 3.1.4.17), by specifically hydrolyzing cyclic nucleotides (Fig. 1), controls cAMP and cGMP levels and mediates their return to the basal state. PDE nomenclature (PDE1 to PDE11) was established according to the genes of which they are products, their biochemical properties, regulation, and their sensitivity to pharmacological agents (Beavo, 1995). Their critical role in intracellular signaling has designated them as potential new therapeutic targets. Several leading pharmaceutical companies are searching for and developing new therapeutic agents on the basis of their ability to potently and selectively inhibit PDE isozymes, notably PDE4 in inflammation and PDE5 in human erectile dysfunction (ED). Nevertheless, the precise mechanism and the contribution of the various PDE isozymes in modulating tissue-specific intracellular signaling remain to be established (Table 1).
The following sections review cyclic nucleotide phosphodiesterase superfamily (properties, regulations, tissue and subcellular distributions, and specific inhibitors) by focusing on their therapeutic potentialities related to their participation in intracellular signaling.
Section snippets
The superfamily of phosphodiesterase
Cyclic AMP phosphodiesterase (cAMP-PDE) activity was first described in 1962 by Butcher and Sutherland, ratifying 3′, 5′-cyclic AMP characterization. Therefore, during the 1970s and 1980s, basic research was focused on the biochemical characterization of PDE activities and on the determination of their functional role. Biochemical characterizations of PDE activities were performed by anion exchange chromatography of tissue cytosolic fractions that allowed the dissociation of various fractions
Phosphodiesterase 1 family
Cheung (1970) and Kakiuchi and Yamazaki (1970) simultaneously discovered from bovine and rat brains, respectively, a calciprotein constituted of 148 aa, as a thermostable factor named calcium-dependent activator or regulator (CDA or CDR) or phosphodiesterase activating factor (PAF), which binds 4 Ca2+ mol/mol. This protein, named calmodulin (CaM), was shown to activate cyclic nucleotide phosphodiesterase in a calcium-dependent manner. This discovery allowed characterizing the first eluted
Specific inhibitors of the phosphodiesterase families
Theophylline was the first inhibitor to be described in the literature in 1962 (Butcher & Sutherland, 1962). One decade later, a new xanthine analogue, 1-methyl-3-isobutylxanthine (IBMX), was shown to be one 100-fold more potent than theophylline (for review, see Chasin & Harris, 1976). Theophylline (Lugnier et al., 1992), as well as IBMX (Lugnier & Komas, 1993), was designed as nonspecific PDE inhibitors since they similarly inhibit PDE1 to PDE5 families. In the last decade, a great number of
Short-term regulation: cross-talk regulations in the cardiovascular system
In the cardiovascular system, it is well established that (i) an increase in cAMP level induces positive inotropic effect in the heart, whereas it induces vasorelaxation; and (ii) an increase in cGMP level decreases cardiac contraction and induces vasorelaxation. Due to their cyclic nucleotide inactivating role, PDEs play a major role in the fine regulation of these functions.
Long-term regulation: phosphodiesterases and endothelial cell proliferation
A comparison of PDE isozymes performed in resting and angiogenic phenotypes of bovine aortic endothelial cells reveals an increase in cAMP hydrolytic activity associated with an increase of PDE transcripts and proteins. The induction of PDE3 and PDE5 indicates that PDE overexpression would participate in angiogenesis (Keravis et al., 2000). Angiogenesis, which is defined as the formation of new blood vessels from preexisting ones, is induced notably by vascular endothelium growth factor (VEGF),
Conclusion
Although ubiquitously distributed in eucaryotes, the PDE superfamilly represents a good opportunity to develop new therapeutic and specific approaches, especially in diseases that remain unresolved, as much as they have multifactorial origins. By hydrolyzing cAMP and/or cGMP, these intracellular enzymes, being at the pathway crossroad, critically control multiple intracellular signaling pathways that can be altered in many pathologies, such as cancer, inflammation, neurodegeneration, oxidative
Acknowledgment
Dr Thérèse Keravis (CNRSUMR 7034, Strasbourg) is greatly acknowledged for her critical reading of the manuscript.
References (380)
- et al.
A prototype of a novel class of orally active anti-inflammatory phosphodiesterase 4 inhibitors
Bioorg Med Chem Lett
(2002) - et al.
Subunit structure of rod cGMP-phosphodiesterase
J Biol Chem
(1996) - et al.
Isolation of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate from rat urine
Biochem Biophys Res Commun
(1963) - et al.
A simple procedure for the long-term cultivation of chicken embryos
Dev Biol
(1974) - et al.
Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD)
Gene
(1994) - et al.
UCR1 and UCR2 domains unique to the cAMP-specific phosphodiesterase family form a discrete module via electrostatic interactions
J Biol Chem
(2000) - et al.
Stimulation of adenosine 3′,5′-monophosphate hydrolysis by guanosine 3′,5′-monophosphate
J Biol Chem
(1971) - et al.
Differentiation of human monocytes in vitro with granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor produces distinct changes in cGMP phosphodiesterase expression
Cell Signal
(2004) - et al.
Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance
Neuropharmacology
(2004) - et al.
Adenosine 3′, 5′-phosphate in biological materials: 1. Purification and properties of cyclic 3′, 5′-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3′, 5′-phosphate in human urine
J Biol Chem
(1962)
Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes
J Biol Chem
Cyclic 3′,5′-nucleotide phosphodiesterase. Demonstration of an activator
Biochem Biophys Res Commun
Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis
Blood
Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling
J Biol Chem
Cyclic nucleotide phosphodiesterase of retinal photoreceptors. Partial purification and some properties of the enzyme
Biochim Biophys Acta
Characteristics of a new binding protein distinct from the kinase for guanosine 3′:5′-monophosphate in rat platelets
Biochim Biophys Acta
Characterization of a novel potent and specific inhibitor of type V phosphodiesterase
Biochem Pharmacol
Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression
FEBS Lett
Purification of the putative hormone-sensitive cyclic AMP phosphodiesterase from rat adipose tissue using a derivative of cilostamide as a novel affinity ligand
J Biol Chem
Protein kinase A anchoring
J Biol Chem
Chelerythrine, a protein kinase C inhibitor, interacts with cyclic nucleotide phosphodiesterases
Eur J Pharmacol
Benzyl vinylogous amide substituted aryldihydropyridazinones and aryldimethylpyrazolones as potent and selective PDE3B inhibitors
Bioorg Med Chem
Molecular cloning and functional expression in yeast of a human cAMP-specific phosphodiesterase subtype (PDE IV-C)
FEBS Lett
Interaction of calcium antagonists with cyclic AMP phosphodiesterases and calmodulin
Biochem Biophys Res Commun
Isolation and differential tissue distribution of two human cDNAs encoding PDE1 splice variants
Cell Signal
Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase
Biochem Biophys Res Commun
Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase
J Biol Chem
Solubilization of membrane-bound rod phosphodiesterase by the rod phosphodiesterase recombinant delta subunit
J Biol Chem
Purification of cGMP-binding protein phosphodiesterase from rat lung
Methods Enzymol
Characterization of a novel cGMP binding protein from rat lung
J Biol Chem
Phosphorylation of isolated human phosphodiesterase-5 regulatory domain induces an apparent conformational change and increases cGMP binding affinity
J Biol Chem
Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)
J Biol Chem
Related Cloning and characterization of the human and mouse PDE7B, a novel cAMP-specific cyclic nucleotide phosphodiesterase
Biochem Biophys Res Commun
Characterization of an in vivo hormonally regulated phosphodiesterase 3 (PDE3) associated with a liver Golgi-endosomal fraction
Arch Biochem Biophys
cAMP-dependent induction of PDE5 expression in murine neuroblastoma cell differentiation
FEBS Lett
Expression of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in mouse tissues and cell lines using an antibody against the enzyme amino-terminal domain
Biochim Biophys Acta
Sustained entry of Ca2+ is required to activate Ca2+ calmodulin-dependent phosphodiesterase 1A (PDE1A)
J Biol Chem
Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor
Bioorg Med Chem Lett
Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle
Biochem Pharmacol
TCR- and CD28-mediated recruitment of phosphodiesterase 4 to lipid rafts potentiates TCR signaling
J Immunol
Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity
J Med Chem
Expression of cGMP-specific phosphodiesterase 9A mRNA in the rat brain
J Neurosci
Selective inhibition of separated forms of human platelet cyclic nucleotide phosphodiesterase by platelet aggregation inhibitors
Mol Pharmacol
A-kinase anchoring proteins interact with phosphodiesterases in T lymphocyte cell lines
J Immunol
Beta-arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi
Proc Natl Acad Sci U S A
Differential expression of PDE4 cAMP phosphodiesterase isoforms in inflammatory cells of smokers with COPD, smokers without COPD, and nonsmokers
Am J Physiol Lung Cell Mol Physiol
Inhibitors of phosphodiesterase IV (PDE IV) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high-affinity rolipram binding site
J Pharmacol Exp Ther
The ability of phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity
J Pharmacol Exp Ther
Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms
Physiol Rev
Nerve growth factor inhibits PC12 cell PDE 2 phosphodiesterase activity and increases PDE 2 binding to phosphoproteins
J Neurochem
Cited by (761)
Almond-citrus peel enriched short bread modulates sexual behaviour and enzymes linked with erectle dysfunction in hypertensive rats
2023, Journal of Agriculture and Food ResearchPPAR/PDK4 pathway is involved in the anticancer effects of cGMP in pancreatic cancer
2023, Biochemical and Biophysical Research CommunicationsDeciphering the therapeutic role of Kigelia africana fruit in erectile dysfunction through metabolite profiling and molecular modelling
2023, Informatics in Medicine UnlockedStrategies for the enhancement of anti-cancer effect of phosphodiesterase type 5 inhibitors using drug binding fusion proteins
2024, Biotechnology and Bioprocess EngineeringPhosphodiesterase-4 Inhibition in the Management of Psoriasis
2024, Pharmaceutics