Associate editor: V. Schini-Kerth
Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents

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Abstract

Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.

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.

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