Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents

Pharmacology & Therapeutics 109 (2006) 366 – 398 www.elsevier.com/locate/pharmthera

Associate editor: V. Schini-Kerth

Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents Claire Lugnier * CNRS UMR, 7034, Pharmacologie et Physicochimie des Interactions Mole´culaires et Cellulaires, Faculte´ de Pharmacie, Universite´ Louis Pasteur de Strasbourg, 74 route du Rhin, BP 60024, 67401 Illkirch, France

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 isozymeselective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects. D 2005 Elsevier Inc. All rights reserved. Keywords: Cyclic AMP; Cyclic GMP; Phosphodiesterase (PDE); Intracellular signaling; Expression; Cell cycle; Disease; Angiogenesis; Inflammation

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The superfamily of phosphodiesterase . . . . . . . . . . . . . . . . . . . . . . . 2.1. Molecular targets of adenosine 3V, 5V-cyclic monophosphate and guanosine 3V, 5V-cyclic monophosphate . . . . . . . . . . . . . . . . . . . . . . . . 2.2. General structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characterization and properties of the various phosphodiesterase families. . . . . 3.1. Phosphodiesterase 1 family . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Functional roles . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Phosphodiesterase 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Tel.: +33 3 902 442 64; fax: +33 3 902 44313. E-mail address: [email protected]. 0163-7258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2005.07.003

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3.2.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Short-term regulation . . . . . . . . . . . . . . . . . . . . 3.2.4. Long-term regulation . . . . . . . . . . . . . . . . . . . . 3.3. Phosphodiesterase 3 family . . . . . . . . . . . . . . . . . . . . . 3.3.1. Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Short-term regulation . . . . . . . . . . . . . . . . . . . . 3.3.4. Functional role . . . . . . . . . . . . . . . . . . . . . . . 3.4. Phosphodiesterase 4 family . . . . . . . . . . . . . . . . . . . . . 3.4.1. Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Short-term regulations. . . . . . . . . . . . . . . . . . . . 3.4.3. Long-term regulation . . . . . . . . . . . . . . . . . . . . 3.4.4. Intracellular compartmentation . . . . . . . . . . . . . . . 3.4.5. Phosphodiesterase 4 isozyme functional roles. . . . . . . . 3.5. Phosphodiesterase 5 . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Short-term regulation . . . . . . . . . . . . . . . . . . . . 3.5.3. Long-term regulation . . . . . . . . . . . . . . . . . . . . 3.5.4. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.5. Functional role . . . . . . . . . . . . . . . . . . . . . . . 3.6. Phosphodiesterase 6 family . . . . . . . . . . . . . . . . . . . . . 3.6.1. Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.2. Short-term regulation . . . . . . . . . . . . . . . . . . . . 3.6.3. Functional roles . . . . . . . . . . . . . . . . . . . . . . . 3.7. Phosphodiesterase 7 family . . . . . . . . . . . . . . . . . . . . . 3.7.1. Phosphodiesterase 7A . . . . . . . . . . . . . . . . . . . . 3.7.2. Phosphodiesterase 7B . . . . . . . . . . . . . . . . . . . . 3.8. Phosphodiesterase 8 family . . . . . . . . . . . . . . . . . . . . . 3.8.1. Phosphodiesterase 8A . . . . . . . . . . . . . . . . . . . . 3.8.2. Phosphodiesterase 8B . . . . . . . . . . . . . . . . . . . . 3.9. Phosphodiesterase 9 . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Phosphodiesterase 10 . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Phosphodiesterase 11. . . . . . . . . . . . . . . . . . . . . . . . . 4. Specific inhibitors of the phosphodiesterase families. . . . . . . . . . . . . 4.1. Phosphodiesterase 1 inhibitors . . . . . . . . . . . . . . . . . . . . 4.2. Phosphodiesterase 2 inhibitors . . . . . . . . . . . . . . . . . . . . 4.3. Phosphodiesterase 3 inhibitors . . . . . . . . . . . . . . . . . . . . 4.4. Phosphodiesterase 4 inhibitors . . . . . . . . . . . . . . . . . . . . 4.5. Phosphodiesterase 5 inhibitors . . . . . . . . . . . . . . . . . . . . 4.6. Phosphodiesterase 6 inhibitors . . . . . . . . . . . . . . . . . . . . 4.7. Phosphodiesterase 7/8/9/10/11 inhibitors . . . . . . . . . . . . . . . 5. Short-term regulation: cross-talk regulations in the cardiovascular system . . 5.1. Phosphodiesterase role in cardiac contraction . . . . . . . . . . . . 5.2. Phosphodiesterase role in vascular contraction. . . . . . . . . . . . 6. Long-term regulation: phosphodiesterases and endothelial cell proliferation . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. 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

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has extensively developed new efficient therapeutic compounds by SAR and graphic computer-aided receptor mapping (Hibert et al., 1988, 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 3V, 5V-cyclic monophosphate (cAMP) and guanosine 3V, 5V-cyclic mono-

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C. Lugnier / Pharmacology & Therapeutics 109 (2006) 366 – 398 X N

X N

N

N

OH 5’

O 4’

N O 3’

O=P OH

N

O=P O

R

1’

OH

PDE

2’

H2O, Mg2+

R Adenine = H Guanine = NH2

N

O

+ H+ R

1’ 3’ 2’ OH OH

O 3’,5’ cAMP/cGMP

5’ 4’

N

5’ AMP/GMP

X NH 2 0

Fig. 1. Cyclic nucleotide hydrolysis by cyclic nucleotide phosphodiesterases.

phosphate (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). Table 1 Classification of the PDE family PDE family Substrate PDE1 PDE2 PDE3 PDE4 PDE5 PDE6 PDE7 PDE8 PDE9 PDE10 PDE11

Property

cAMP, cGMP Ca-calmodulinactivated cAMP, cGMP cGMP-activated, cAMP, cGMP cGMP-inhibited cAMP cGMP-insensitive

Specific inhibitors Nimodipine

EHNA Cilostamide, milrinone Rolipram, Ro 20-1724, roflumilast cGMP PKA/PKGZaprinast, DMPPO, phosphorylated E4021, Sildenafil cGMP Transducin-activated Zaprinast, DMPPO, E4021, Sildenafil cAMP Rolipram-insensitive BRL 50481, ICI242 cAMP Rolipram-insensitive Unknown IBMX-insensitive cGMP IBMX-insensitive Unknown cAMP, cGMP Unknown Unknown cAMP, cGMP Unknown Unknown

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.

2. The superfamily of phosphodiesterase Cyclic AMP phosphodiesterase (cAMP-PDE) activity was first described in 1962 by Butcher and Sutherland, ratifying 3V, 5V-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 of PDE activities. These fractions were differentiated by their substrate specificity (Thompson & Appleman, 1971) and sensitivity to calcium – calmodulin (CaM) and were numbered according to elution order (Wells et al., 1975), PDE I represented mainly calmodulin-activated PDE activity. PDE characterization in tissues and cell extracts grew extensively. Since the properties, functional role (Lugnier et al., 1983), as well as distribution (1 PDE isozyme missing in some tissues) of PDE activity differed from 1 tissue to the other, some confusion appeared in the literature concerning PDE nomenclature. Furthermore, characterization of inhibitors, activators, or ligands that act preferentially on 1 isozyme allowed discrimination of new PDE isozymes and lead investigators to give new names for various PDE isozymes, such as ROI-PDE (rolipram-inhibited PDE), CGI-PDE (cGMP-inhibited PDE), CaM-PDE (calmodulin-activated PDE), cGS-PDE (cGMP-stimulated PDE), and cGB-PDE (cGMP-binding PDE). Altogether, these increasingly confusing data and the beginning in the 1990s of PDE cloning induced PDE leaders to establish an official nomenclature for PDE isozymes, initiated by Beavo (1995). For example, HSPDE13A2A:

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‘‘The first 2 letters represent the species, for example, HS for Homo sapiens. The next 3 letters plus 1 or 2 Arabic numerals designate the cyclic nucleotide phosphodiesterase gene family. The next letter represents the individual gene product within the family. The final Arabic numeral represents the splice variant, and the final letter allows GenBank to assign a unique locus field designation based on when the entry was submitted and also to give different locus names to conflicting or incomplete sequences’’ (http:// www.depts.washington.edu/pde/Nomenclature.html). According to this nomenclature ‘‘PDE13’’, ‘‘PDE13A’’, and more precisely, ‘‘PDE13A2’’ are now currently used in the literature and are used herein. Presently, 11 PDE families are identified and cloned, constituting the extent of the superfamily of PDE (for review, see Conti, 2000; Soderling & Beavo, 2000; Francis et al., 2001; Mehats et al., 2002).

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nucleotide exchange factors (cAMP-GEFS) were newly discovered as a Rap1 guanine-nucleotide-exchange factor that is activated directly by cAMP (de Rooij et al., 1998). Cyclic nucleotide-gated (CNG) ion channels were first discovered in rod photoreceptors (Cook et al., 1987), where they are responsible for the primary electrical signaling of the photoreceptor in response to light. CNG channels are highly specialized membrane proteins that open an ionpermeable pore across the membrane in response to the direct binding of intracellular cyclic nucleotides (for review, see Kaupp & Seifert, 2002; Matulef & Zagotta, 2003). As described below, PDE isozymes such as PDE2 and PDE3 are activated or inhibited by cGMP, whereas PDE10 is potently inhibited by cAMP, allowing significant cross-talk between PDEs. 2.2. General structure

2.1. Molecular targets of adenosine 3V, 5V-cyclic monophosphate and guanosine 3V, 5V-cyclic monophosphate Cyclic nucleotides, inactivated by PDEs, regulate multiple intracellular targets, protein kinase A (PKA), protein kinase G (PKG), exchange protein directly activated by cAMP (EPAC), cyclic nucleotide-gated channel (CNG), as well as PDEs themselves (Fig. 2). The best documented of these targets are the cyclic nucleotide dependent protein kinases, protein kinases A (PKA) and protein kinases G (PKG), that are directly activated by cAMP and cGMP, respectively. They control functional cellular responses such as intracellular calcium, cell proliferation, inflammation, and transcription (for review, see Francis & Corbin, 1999). Since some of them are attached to different cellular ultrastructures via specific A kinase anchoring proteins (AKAPs, Dell’Acqua & Scott, 1997) or G kinase anchoring proteins (GKAPs, Vo et al., 1998), they participate in intracellular signaling compartmentation (Wong & Scott, 2004). Moreover, cAMP and cGMP were shown to cross-activate PKG and PKA, respectively (Forte et al., 1992; Jiang et al., 1992). Among the direct cAMP targets, EPAC or cAMP-regulated guanine

cAMP

EPAC (cAMP-GEF)

PKA

cGMP

CNG

PKG

GAF (PDE2, PDE5, PDE6) (PDE10, PDE11)

Fig. 2. Molecular targets of cyclic nucleotides. cAMP directly activates cAMP-guanine nucleotide-exchange factor (EPAC), protein kinase A (PKA), as well as the cyclic nucleotide-gated channel (CNG). cGMP directly activates protein kinase G (PKG), and CNG interacts with the cGMP-binding domains (GAF) of PDE2, PDE5, PDE6, PDE10, and PDE11. Furthermore, cAMP and cGMP can cross-activate PKG and PKA, respectively.

The different mammalian PDEs share common structural determinants: a catalytic domain encompassing a region of ¨ 270 amino acids (aa); a regulatory domain between the amino terminus and the catalytic domain on which are located calmodulin binding sites for PDE1, allosteric cGMP binding sites, that is, GAF domains for PDE2, PDE5, PDE6, PDE10, and PDE11 (for review, see Ho et al., 2000; Zoraghi et al., 2004), phosphorylation sites, phosphatidic binding site for PDE4, PAS domain for PDE8, autoinhibitory sequences for PDE1 and PDE4, and a membrane association domain for PDE2 – 4, as well as dimerization motifs; and a domain which can be prenylated or phosphorylated by MAPKinase of as yet undetermined function between the catalytic domain and the carboxy terminus (Fig. 3). The catalytic domain, which constitutes the core of PDE, is a highly conserved region, with a 20– 45% identity. It includes consensus metal binding domains: 2 Zn2+ binding motifs Hx3Hxn E/D and a Mg2+ binding motif related to metal – ion phosphohydrolases (Francis et al., 2001). This domain is encoded by related, but distinct genes, suggesting evolution from a common ancestor before the separation of sponges and eumetozoans, about 940 million years ago (Koyanagi et al., 1998). Each family encompasses 1 to 4 distinct genes to give more than 20 genes in mammals. Each gene encodes multiple protein products generated by alternative splicing and/or the use of multiple promoters, with more than 50 different PDE proteins probably produced in mammalian cells. This multiplicity of PDE proteins may allow specific intracellular localization of PDEs in the vicinity of various protein effectors inducing fine-tuning of compartmentalized regulation for cAMP and cGMP. In that way, we have shown by biochemical isolation and histochemical studies that in cardiac tissues, beside their cytosolic distribution, PDE2, PDE3, and PDE4 are associated to sarcolemma (Okruhlicova et al., 1996, 1997, 1998), PDE3 is mainly associated to the sarcoplasmic reticulum (Lugnier et al., 1993), PDE2 and PDE3 to Golgi endosome (Geoffroy et

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C. Lugnier / Pharmacology & Therapeutics 109 (2006) 366 – 398 PKA, CaMK P

PDE1A,B,C Ca/CaM

Ca/CaM

cGMP

cGMP

PDE2A

PKA, PKB P P

PDE3A,B

44 aa insert

Membrane-associated domain

PKA

ERK2

P

PDE4A,B,C,D

PDE6A,B,C

PDE8A,B

UCR1 LR1 UCR2

LR2

cGMP

PDE5A

PDE7A,B

Targeting domain

P

GAF A

GAF B

GAF A

GAF B

Targeting domain

PAS domain

PDE9A

REC

PDE10A

GAF A

GAF B

PDE11A

GAF A

GAF B

Fig. 3. Structures of the different PDE families constituting the PDE superfamily. Adapted from Conti (2000).

Fig. 4. Subcellular distribution of PDE families in cardiac tissues.

C. Lugnier / Pharmacology & Therapeutics 109 (2006) 366 – 398

al., 1999), and PDE4 to nucleus envelope (Lugnier et al., 1999b; Fig. 4).

3. Characterization and properties of the various phosphodiesterase families 3.1. 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 fraction of PDE activity (Peak 1 or PDE I) isolated by chromatography from vascular smooth muscle. Since this PDE I fraction was specifically activated by Ca2+/CaM, it was also named CaM-PDE (Wells et al., 1975). The cooperative binding of 4 Ca2+ to calmodulin is required to fully activate CaM-PDE (Huang et al., 1981). 3.1.1. Structure Today, 3 genes with various splice variants constitute PDE1 family (for review, see Wang et al., 1990; Kakkar et al., 1999; Fidock et al., 2002). These soluble enzymes are homodimerics. In this unique CaM-sensitive PDE family, sensitivity to calcium and calmodulin varies from 1 variant to the other (Sonnenburg et al., 1995; Yan et al., 1996). Furthermore, the phosphorylation of PDE1A1 (59 kDa) and PDE1A2 (61 kDa) by PKA (Sharma & Wang, 1985; Sharma, 1991; Sonnenburg et al., 1995) and of PDE1B1 (63 kDa) by CaM Kinase II (Sharma & Wang, 1986; Hashimoto et al., 1989) decreases their sensitivity to calmodulin activation. This effect is much greater on the PDE1A than on PDE1B1. These changes also induce a change in Ca2+ sensitivity since, at a saturating concentration of CaM (micromolar range), the activation of the phosphorylated isozyme requires a significantly higher concentration of Ca2+ than the corresponding nonphosphorylated form (Wang et al., 1990). According to their gene and splice variants, PDE1s differently hydrolyze cAMP and cGMP. For instance, PDE1C, having a much higher K m for cAMP than for cGMP, preferentially hydrolyzes cGMP. 3.1.2. Regulation In cells expressing PDE1, hormones that increase cytosolic Ca2+ would activate PDE1, decreasing thereby cyclic AMP in response to hormones that stimulate cAMP or cGMP synthesis. It was recently shown that sustained Ca2+ entry in the cell is required to activate PDE1A in astrocytoma cell line and that PDE1A cannot discriminate

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between the different sources of Ca2+ entry (Goraya et al., 2004). In contrast, in vivo phosphorylation of PDE1 would likely result in the potentiation of cAMP or cGMP accumulation involving the elevation of cytosolic Ca2+ and activation of guanylyl or adenylyl cyclases and would play a major role in the amplification and prolongation of cyclic nucleotide effects. In this regard, PDE1 might contribute to certain forms of synaptic plasticity in neurons. PDE1 is mainly present in cytosolic fraction; nevertheless, it was shown that PDE1 is also found in the fibers of several neurons from dorsal root ganglion (Giorgi et al., 2002). 3.1.3. Distribution PDE1A is highly present in the brain. In human spermatozoa, PDE1A is tightly associated to calmodulin and will be therefore permanently activated (Lefie`vre et al., 2002). PDE1B1 mRNA is found predominantly in the human brain at the level of neuronal cells of the cerebellum, hippocampus, caudate, and Purkinje cells, its expression is correlated with brain regions having extensive dopaminergic innervation and D1 dopamine receptor mRNA (Polli & Kincaid, 1992). PDE1B1 is also found in the heart and skeletal muscle (Yu et al., 1997). PDE1C1 mRNA is mainly expressed in the brain and the heart (Loughney et al., 1996) and seems to be the major type highly expressed in the mouse cerebellar granular cells (Yan et al., 1996). PDE1C2 represents the high-affinity CaM-PDE in olfactory epithelium (Yan et al., 1995) and PDE1C1 and PDE1C4/5 mRNA are present in the testis (Yan et al., 1996). These different specific distributions concerning the various subtypes of PDE1 will contribute to the regulation of specific cellular functions. 3.1.4. Functional roles For instance, PDE1A1 was reported to be up-regulated in rat aorta with the development of nitrate tolerance (Kim et al., 2001). PDE1B mRNA is induced in PHA or anti-CD3/ CD28-activated human T-lymphocytes and participates in IL-13 regulation implicated in allergic diseases (Kanda & Watanabe, 2001). Studies performed in permanent cell lines suggest that the inhibition of PDE1B1 may induce apoptosis in human leukemic cells (Jiang et al., 1996), the induction of PDE1C promotes arterial smooth muscle cell proliferation (Rybalkin et al., 2002), and PDE1C down-regulates glucose-induced insulin secretion (Han et al., 1999). Transgenic mouse generation would help to define a specific function of PDE isozyme. In that way, it is shown that PDE1B knockout mice exhibit exaggerated locomotor hyperactivity in response to dopamine agonist and display impaired spatial learning (Reed et al., 2002). These different alterations in tissue and cell PDE1 isozymes may occur by short-term (phosphorylation, proteolysis) or long-term regulation (at the mRNA level) in response to hormonal stimulation and should play on spatio-temporal regulation of PDE1 activity. In that way, stage and cell-specific expressions of PDE1 isozymes were

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shown in mouse testis (Yan et al., 2001). Furthermore, a rapid transient induction of PDE1B isozyme was shown in CHO cells through receptor-mediated stimulation of lipid signaling pathways (Spence et al., 1997). Characterization by cDNA screening of 13 splice variants for human PDE1A (Michibata et al., 2001) raises the question on their functional role and on the knowledge of their respective promotor to clarify the molecular pathway for their regulations and to understand their participation in various diseases. 3.2. Phosphodiesterase 2 PDE2, firstly named cGMP-stimulated PDE (cGS-PDE), was discovered by Beavo et al. (1971) by adding cGMP during cAMP-PDE assay to rat liver supernatant or to crude particulate fractions from various rat tissues (for review, see Manganiello et al., 1990). Studies performed on purified PDE2 clearly showed that PDE2 hydrolyzes both cAMP and cGMP and is allosterically regulated by cAMP and cGMP with positive cooperative kinetics, with cGMP being preferred both as substrate and effector (Erneux et al., 1981). In the presence of cGMP, the rate of cAMP hydrolysis is increased by 6-fold (Martins et al., 1982). At physiological concentrations of cyclic nucleotides, PDE2 responds to elevated cGMP with increased hydrolysis of cAMP. PDE2 was shown to play a major feedback role by restoring the basal level in cyclic nucleotides in response to hormonal stimulation in the adrenal gland (MacFarland et al., 1991). 3.2.1. Structure PDE2 cloning allowed to unequivocally confirm and precise the previous biochemical properties established by various teams for purified PDE2 enzymes from bovine heart (Martins et al., 1982), adrenal tissue (Martins et al., 1982; Miot et al., 1985), liver (Pyne et al., 1986), and brain cortex (Whalin et al., 1988; Murashima et al., 1990). PDE2 was characterized in platelets (Asano et al., 1997) as well as endothelial cells (Lugnier & Schini, 1990). Presently, 3 variants of a single gene were cloned for PDE2: PDE2A1 (Sonnenburg et al., 1991), PDE2A2 (Yang et al., 1994), and PDE2A3 (Rosman et al., 1997). They share the same C-terminal sequence, but differ by their amino termini, which may be responsible for particulate or soluble localization. Two GAF domains, GAF-A and GAF-B, were identified on the N-terminal domain of the PDE2A subunit (100 – 105 kDa) having distinct roles in dimerization and in cGMP binding, respectively (Martinez et al., 2002). A study aimed to characterize the molecular determinant for cyclic nucleotide binding suggests that cGMP binding to GAF-B activates the enzyme rapidly and stoichiometrically in an all-or-none fashion (Wu et al., 2004). This would be important for signalization in tissues containing a high level of PDE2 and in which very rapid cyclic nucleotide changes have been seen, such as the

heart (Keely & Corbin, 1977) and platelets (Haslam et al., 1999). PDE2 has a functional role in the heart since it was shown that PDE2 regulates basal calcium current in human atrial myocytes (Rivet-Bastide et al., 1997). Since NO increases cGMP levels by stimulating particulate guanylyl cyclase, PDE2 activation can mediate functional response to NO in permanent cell line (Schrofner et al., 2004) as well as in rat cardiac fibroblasts (Gustafsson & Brunton, 2002) and participate in the regulation of endothelial permeability (Suttorp et al., 1996). Furthermore, it was shown on 1 hand that consecutively to in vivo PMA stimulation, PDE2 could be activated by PKC (possibly by phosphorylating PDE2, Geoffroy et al., 1999), and, on another hand, that NGF inhibits cell PDE2 activity by increasing its binding to phosphoproteins (Bentley et al., 2001). 3.2.2. Distribution PDE2 protein is mainly present in adrenal medulla, heart, rat ventricle (Yanaka et al., 2003), brown adipose tissue (Coudray et al., 1999), liver, and brain. Brain PDE2 is localized in the olfactory epithelia (Juilfs et al., 1997), in olfactory sensory neurons (Meyer et al., 2000), bulb and tubercle, hippocampus pyramidal, and granule cells (Van Staveren et al., 2003, 2004). PDE2 proteins and mRNAs were characterized in bovine (Keravis et al., 2000), human (Sadhu et al., 1999; Favot et al., 2004), and endothelial cells, media layer of the main pulmonary artery (Pauvert et al., 2002), and macrophages (Bender & Beavo, 2004), Furthermore, in the same specie, endothelial PDE2 distribution varies according to tissue localization (Sadhu et al., 1999). PDE2 is cytosolic or associated to functional membrane structures: plasma membrane, sarcoplasmic reticulum (Lugnier et al., 1993), Golgi (Geoffroy et al., 1999), as well as nuclear envelope (Lugnier et al., 1999a, 1999b). These localizations will be responsible for specific compartmentalized regulation of determined cellular functions depending on cyclic nucleotide levels. 3.2.3. Short-term regulation PDE2 activity is up-regulated in vivo at post-transcriptional level by PKC under 4 beta-phorbol 12-myristate 13acetate (Geoffroy et al., 1999). Furthermore, PDE2 was also up-regulated in rat ventricle in response to pressure overload (Yanaka et al., 2003). Under pathophysiological changes, PDE2 is not only regulated at the post-transcriptional level but also at transcriptional level. 3.2.4. Long-term regulation In endothelial cells, PDE2A is up-regulated during phenotype changes (Keravis et al., 2000) as well as under stimulation by vascular endothelium growth factor (VEGF; Favot et al., 2004), indicating PDE2 participation in endothelial cell proliferation. In another way, PDE2 mRNA and proteins are increased in brown adipose tissue of obese rat (Coudray et al., 1999).

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PDE2 would play a major feedback role by restoring the basal level in cyclic nucleotide in response to hormonal stimulation and would participate in a cross-talk between cAMP and cGMP when present in the cell. The development of specific and potent selective PDE2 inhibitors, as well as PDE2 transgenic mice, will be helpful to precise PDE2 implication in pathophysiology. 3.3. Phosphodiesterase 3 family This enzyme, designated as new cardiotonic drug target in the eighties, was firstly named cAMP-PDE, PDE III, or PDE IV, according to its elution order, and then cGI-PDE. The discovery of rolipram, both as tissue selective inhibitor (Lugnier et al., 1983) and as potent selective inhibitor for cAMP-PDE in regard to CaM-PDE and cGMP-PDE (Lugnier et al., 1986), has allowed to pharmacologically distinguish soluble and membrane associated PDE III (Weishaar et al., 1987) and to separate by chromatography the soluble cardiac cAMP-PDE in 2 fractions: ROI-PDE (rolipram-inhibited PDE) and cGI-PDE (cGMP-inhibited PDE; Komas et al., 1989). The PDE3 enzyme was initially found mainly in the heart, liver, platelet, and adipocyte. Beavo’s and Manganiello’s teams first purified PDE3 from the heart and platelet to homogeneity (Harrison et al., 1986; Macphee et al., 1986; Degerman et al., 1987). PDE3 is characterized by its high affinity for cAMP and its capacity to hydrolyze both cAMP and cGMP, with K m values in submicromolar ranges (K m cAMP= 0.2 AM, K m cGMP= 0.1 AM). Since PDE3 hydrolyzes cAMP with a rate 10-fold greater than for cGMP hydrolysis, and since it has a greater affinity for cGMP, cGMP behaves as a competitive inhibitor of cAMP (for review, see Beavo, 1995). This property contributes to various NO-induced cAMP/cGMP cross-talks in the platelet (Maurice & Haslam, 1990), in vascular smooth muscle intracellular signaling (Komas et al., 1991a, 1991b), and in cardiac myocytes (Fig. 6). PDE3 plays a major role in cardiac contraction by modulating Ca2+ entry consecutively to cAMP-dependent phosphorylation of voltage-gated Ca2+ channel (Fischmeister & Hartzell, 1990). Furthermore, PDE3 inhibition was shown to be the mechanism by which NO stimulates renin secretion from the kidney (Kurtz et al., 1998). PDE3 could be either cytosolic or membrane bound. It was shown to be associated to plasma membrane (Okruhlicova et al., 1996, 1997), sarcoplasmic reticulum (Lugnier et al., 1993), Golgi apparatus (Geoffroy et al., 2001), as well as associated to nucleus envelope (Lugnier et al., 1999b). These different PDE3 distributions support FRET revelation for distinct functions of compartmentalized phosphodiesterases (Mongillo et al., 2004). 3.3.1. Structure PDE3 cloning reveals 2 genes with various splices constitute that PDE3 family. Both PDE3 isoforms are structurally similar, containing an NH2-terminal domain

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important for the localization of the enzyme to particulate fraction and catalytic domain at the carboxy terminus end. PDE3 catalytic domain, in opposite to all other PDEs, is characterized by a 44-aa insert that may be involved in cGMP-PDE3 sensitivities (He et al., 1998). PDE3A is more sensitive to cGMP than PDE3B is. 3.3.2. Distribution PDE3A is mainly present in the heart, platelet, vascular smooth muscle, and oocyte, whereas PDE3B is mainly associated to adipocytes, hepatocytes, and spermatocytes. Myocardial human cDNA PDE3A was cloned, encoding a protein of 125 kDa (Meacci et al., 1992). PDE3A gene results in the generation of 2 mRNAs (PDE3A1 and PDE3A2) and 3 proteins (136 kDa generated from PDE3A1 mRNA and 118 and 94 kDa, both generated from PDE3A2 mRNA) in cardiac myocytes that differ with respect to intracellular localization and regulation (Wechsler et al., 2002). Cloned human platelet PDE3A was identical to the cloned enzyme from the heart (Cheung et al., 1996). PDE3A was cloned from mouse oocyte, encoding a soluble enzyme of 135 kDa (K m = 0.2 AM; Shitsukawa et al., 2001). 3.3.3. Short-term regulation Short-term activation of PDE3 was firstly demonstrated in rat fat cells in response to insulin and isoprenaline stimulations, which induce PDE3 phosphorylation (Degerman et al., 1990). A single phosphorylated serine site (Ser 302) was identified (Rahn et al., 1996), This site could be phosphorylated either by PKA or by PKB, but the major site of PKB phosphorylation is Ser 273 (Kitamura et al., 1999). The possible activation of PDE3B by PI3-K phosphorylation (Rondinone et al., 2000) was recently implicated in the hypothalamic action of leptin on feeding (Zhao et al., 2002) as well as in h-cell insulin secretion (Zhao et al., 1998). Furthermore, hormonal stimulation (insulin, glucagon) was shown to activate in vivo PDE3 associated to Golgiendosomal fraction (Geoffroy et al., 2001). 3.3.4. Functional role PDE3A-deficient mice, although being viable and ovulated in a normal number of oocytes, are completely infertile, indicating that the resumption of meiosis requires PDE3A activity (Masciarelli et al., 2004). Human adipocyte PDE3B cDNA encodes a protein of 123 kDa (Miki et al., 1996). Today, only 1 PDE3B mRNA is known encoding only for 1 PDE3B protein. When overexpressed in mice h-cells, PDE3B causes impaired insulin secretion and glucose intolerance, alterations that reflect type 2 diabetes (Harndahl et al., 2004). Nevertheless, identified polymorphisms in the 5V flanking region of the human PDE3B gene are unlikely to have major effects on susceptibility to Japanese type 2 diabetes (Osawa et al., 2003). The 3-dimensional structure of the catalytic domain of human PDE3B in complex with PDE3 inhibitor was

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recently reported providing molecular basis for inhibitor specificity (Scapin et al., 2004). 3.4. Phosphodiesterase 4 family PDE4, a cAMP-specific PDE, previously named cAMPPDE, ROI-PDE, and PDE IV, is mainly present in the brain (for review, see Houslay et al., 1998), inflammatory cells (Tenor & Schudt, 1996), cardiovascular tissues (for review, see Stoclet et al., 1995), and smooth muscles but is lacking in the platelets. PDE4 was shown to be specifically inhibited by rolipram (K i = 0.8 AM) and Ro-201724 and to be insensitive to cGMP (Lugnier et al., 1983, 1986), allowing pharmacological discrimination of PDE4 family from PDE3 family (Weishaar et al., 1987; Komas et al., 1989). In another way, the antidepressant agent rolipram binds with high affinity to rat brain, questioning the link between highaffinity rolipram-binding site and PDE4 (Schneider et al., 1986). 3.4.1. Structure Presently, the PDE4 family represents the largest PDE family, constituted by 4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) with various alternative mRNA splices encoding long PDE4 and short PDE4 isozymes, at least 35 different PDE4 proteins (Swinnen et al., 1989; Livi et al., 1990; Bolger et al., 1993; McLaughlin et al., 1993; Obernolte et al., 1993; Baecker et al., 1994; Sullivan et al., 1994; Engels et al., 1995; Owens et al., 1997). The structure, function, compartmentation, and regulation of PDE4 family were exhaustively investigated by the Marco Conti and Miles Houslay teams by using transgenic mice, molecular biology, GFP-fused protein, and cellular confocal study. The PDE4 family, which exclusively hydrolyzes cAMP (K m = 2 –4 AM), contains a unique signature region of amino acid sequence, called upstream conserved region 1 and 2 (UCR1 and UCR2, Bolger et al., 1993). Long PDE4 isozymes exhibit both UCR1 and UCR2, whereas short PDE isozymes lack UCR1 (Houslay et al., 1998). UCR1 and UCR2 are located between the extreme amino-terminal and the catalytic regions of PDE4 enzymes. LR1 connects UCR1 to UCR2 and LR2 connects UCR2 to the catalytic domain (Fig. 2). They may form a discrete module interacting via electrostatic interactions, which regulate PDE4 catalytic region (Beard et al., 2000). Torphy’s team (Torphy et al., 1992) clearly shows that human PDE4 coexpressed cAMP-PDE activity and high-affinity roliprambinding, indicating that both properties are related to the same protein. Rolipram, the prototypic PDE4 inhibitor, binds to PDE4 in 2 sites, termed low-affinity rolipram binding site (LARBS) and high-affinity binding site (HARBS; Schneider et al., 1986; Jacobitz et al., 1996). It was proposed that anti-inflammatory effect is associated to LARBS whereas emesis is related to HARBS (Barnette et al., 1995a, 1995b). Mutagenesis studies on human recombi-

nant PDE4 performed to identify HARBS reveal that amino acids 265 –332 may form HARBS that is outside of the catalytic domain (aa 591– 661), which was also designated as a low-affinity binding site. Another possibility is that aa 265– 332 may be required for the recombinant enzyme to assume a conformation that binds rolipram to the catalytic domain with high affinity (Jacobitz et al., 1996). In that way, it was further proposed that PDE4 might exist in 2 distinct conformers (Muller et al., 1996; Souness & Rao, 1997). However, the high-affinity binding site requires both the Nterminal domain and the catalytic domain, while the lowaffinity binding state requires only the catalytic domain (Rocque et al., 1997). Furthermore, with PDE4s being metallohydrolases like others PDEs, it was shown by FRET that LARBS PDE4 conformer corresponds to the apoenzyme (metal ion-free), whereas HARBS corresponds to the holoenzyme (metal ion-associated; Laliberte´ et al., 2000; Liu et al., 2001a, 2001b). PDE4, like other PDEs, may exist as a dimer. Since UCR module mediates dimerization, only long-form PDE4 splice variants containing UCR1 and UCR2 are dimerized (Richter & Conti, 2004). 3.4.2. Short-term regulations PDE4 activity is regulated by phosphorylation, association to protein or endogenous mediator, as well as proteolysis. The presence of an acceptor site in UCR1 for PKA-mediated phosphorylation allows a rapid change in PDE4 activity. In vivo, this increase of PDE4 activity was shown as a result of a prolonged elevation of cAMP resulting from hormonal stimulation, and it was proposed and shown to be a short-term feedback mechanism allowing cAMP level to return to basal cellular state (Sette et al., 1994; Oki et al., 2000). Dimerization was shown to be a requisite for the activation of PDE4 long forms by PKA phosphorylation, indicating that dimerization stabilizes PDE4 long forms in their high-affinity rolipram binding conformation (Richter & Conti, 2004). Furthermore, the association of PDE4A4 with SRC family tyrosine kinases in intact cells, by SH3 interaction with the LR2 region of PDE4A, alters the conformation of the PDE4 catalytic unit, increasing it sensitivity to rolipram (McPhee et al., 1999). Phosphatic acid (PA), produced as a result of the stimulation of lipid-signaling pathways, activates long forms of PDE4 (4A5, 4B1, and 4D3), without acting on short forms of PDE4 (4A1, 4B2, 4D1, and 4D2; Nemoz et al., 1997). It is suggested that PA binding to UCR1 alters the conformation of the hydrophobic region triggering for enzyme activation (Houslay et al., 1998). PKA phosphorylation and PA binding sites, as well-dimerizing sites, are located at the N-terminal end of PDE4, whereas ERK phosphorylation sites are located at the carboxy-terminal end of the catalytic region associated to a threonine residue (Houslay et al., 1998; Richter & Conti, 2004). ERK2 (p42MAPK) phosphorylation induces the activation of PDE4D short forms whereas it induces the inhibition of long forms. PDE4 enzymes may play a

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key role for integrating the ERK and cAMP signaling pathways (MacKenzie et al., 2000). 3.4.3. Long-term regulation A prolonged accumulation of cAMP induces a long-term regulation of PDE4 related to PDE4 induction. Swinnen et al. (1991) showed in rat Sertolli cells the specific induction of the short forms PDE4D1 and PDE4D2 consecutively to follicle-stimulating hormone (FSH) or dibutyryl cAMP treatment, whereas the expression of the long-form PDE4D3 was unchanged. They suggested that the PDE4D gene had 2 distinct transcriptional units, the unit controlling the shortform expression being up-regulated by cAMP (Conti et al., 1995). In the same way, cAMP dependent up-regulation was shown for PDE4A in U937 (Torphy et al., 1995) and for PDE4B2 in human monocytes (Manning et al., 1996), in U937 (Torphy et al., 1995), as well as, more recently, in human myometrial cells (Oger et al., 2002). Furthermore, the down-regulation of PDE4A and PDE4B could be associated with PDE4D up-regulation, as shown in endothelial cells during phenotypic change (Keravis et al., 2000), whereas PDE4A was up-regulated and PDE4B and PDE4D were down-regulated in the brain during fluoxetine treatment (Miro et al., 2002). 3.4.4. Intracellular compartmentation The multiplicity of the different PDE4 subtypes favors a differential expression of distinct forms in the different regions and subcellular compartments of rat brain (Iona et al., 1998). The N-terminal end participates to membranebound localization of PDE4. Besides the different subcellular distributions shown for PDE4 described above, it was shown that the long PDE4A3 isozyme binds A-kinase anchoring protein (AKAP), facilitating its phosphorylation by PKA (Dodge et al., 2001). It was also demonstrated that myomegalin, a protein expressed in skeletal and cardiac tissues, anchors PDE4 in the Golgi/centrosomal region of the cell, nearby PKA and its anchoring protein AKAP, to control the state of activation of PKAs (Verde et al., 2001). Changes in the localization of PDE4 are shown to be associated with cell stimulation modifying cell signaling. For instance, in vascular smooth muscle cells, simultaneous activation of PKA and PKC –Raf – MEK – Erk pathways allows for a coordinated activation of PDE4D3 and localization of the particulate PDE4D3 to soluble fraction of these cells (Liu & Maurice, 1999). Furthermore, the specific recruitment of PDE4 to lipid rafts during T-cell activation was shown to serve to abrogate the negative feedback by cAMP, allowing the potentiation of T-cell immune response (Abrahamsen et al., 2004). In cardiac myocytes, PDE4 could be recruited by receptor stimulated h-arrestin to regulate h-adrenoceptor switching from Gs to Gi (Baillie et al., 2003). In another way, during apoptosis, caspase-3 is able to cleave the N-terminal region of PDE4A5, downstream its SH3 interaction domain, altering its intracellular targeting and its catalytic activity (Huston et al., 2000).

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Altogether, the biochemical properties, targeting, and fine-tuned and complex regulations of the different PDE4 isozymes underline PDE4 as critical components of cyclic AMP signaling (Conti et al., 2003), PDE4 orchestrating signaling cross-talk, desensitization and compartmentalization (Houslay & Adams, 2003). 3.4.5. Phosphodiesterase 4 isozyme functional roles PDE4 transgenic mice engineered by Conti and coworkers unequivocally demonstrate the functional roles of PDE4 isozymes. PDE4D-deficient mice are characterized by delayed growth as well as reduced viability and female fertility (Jin et al., 1999). PDE4D knockout mice have an antidepressant-like profile, suggesting that PDE4D-regulated cAMP signaling may play a role in the pathophysiology and pharmacotherapy of depression (Zhang et al., 2002a, 2000b). These mice do not develop airway hyperreactivity to cholinergic stimulation despite an apparently normal lung inflammatory infiltration in response to antigen, providing a rationale for developing new therapies for asthma (Hansen et al., 2000). However, the deletion of PDE4D specifically results in a behavior correlated to emesis, supporting the hypothesis that the inhibition of PDE4D is likely responsible for emesis induced by PDE4 inhibitors (Robichaud et al., 2002). This latter PDE4D function will deserve the use of specific inhibitor of PDE4D as an anti-inflammatory compound. Opposite to PDE4D, PDE4B was shown to be essential for LPS-activated TNF-a responses since, in deficient PDE4B mice, lipopolysaccharide (LPS) stimulation failed to induce TNF-a secretion and mRNA accumulation (Jin & Conti, 2002), indicating that a PDE4B inhibitor would be an anti-inflammatory drug without emetic adverse effects. According to the essential participation of PDE4 subtypes in various cell functions and their critical role in pathophysiology, a great interest in crystallographic data concerning PDE4 X-ray crystal structure was shown by great pharmaceutical companies to perform structure-assisted drug design for specific PDE4 isozyme inhibitors. The crystal structure of the catalytic domain of PDE4B complexed with AMP, 8-Br-AMP, and rolipram was recently reported (Xu et al., 2004), showing that all ligands bind in the same hydrophobic pocket and can interact with the active site metal ions, as previously shown for PDE4B complexed with cAMP (Xu et al., 2000). The crystal structure of the PDE4D2 catalytic domain complexed with AMP revealed that PDE4D2 contains 16 a helices with the same folding as PDE4B. AMP-complexed PDE4D2 catalytic domains are tightly associated into tetramer in the crystal (Huai et al., 2003), but this does not preclude on native PDE4D2 ologomeric structure, since previous structural data reported for PDE4D complexed with zardaverine (a PDE3/PDE4 inhibitor) showed dimerization in hexameric unit (Lee et al., 2002a, 2002b) and that crystal structures concern only catalytic domain.

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3.5. Phosphodiesterase 5 PDE5, previously named cGMP-PDE, cGMP-bindingcGMP-specific phosphodiesterase (cG-BPDE), or PDE V, was firstly characterized as a cGMP-binding protein different from protein kinase co-purifying with a cGMPphosphodiesterase in rat platelets (Hamet & Coquil, 1978; Coquil et al., 1980) and in rat lung (Francis et al., 1980; Francis & Corbin, 1988). In human, bovine, and rat vascular smooth muscle, PDE5 was purified and characterized as a cytosolic PDE isozyme that specifically hydrolyzes cGMP without being activated by Ca/calmodulin and specifically inhibited by compound M&B 22948, presently named zaprinast, the archetype for PDE5 inhibitor, and insensitive to rolipram (Lugnier et al., 1986). Thomas et al. (1990) purified cG-BPDE from bovine lung to homogeneity. It was shown to be a homodimer of 93 kDa subunit, which binds 0.93 mol of cGMP/mol of subunit, and is inhibited by zaprinast and insensitive to rolipram. The use of zaprinast to pharmacologic alleviation of PDE5 activity has allowed investigating the various functional participation of PDE5. 3.5.1. Structure McAllister-Lucas et al. (1993) deduced the structure of bovine lung cG-BPDE from a cDNA clone. The sequence (875 aa) contained a segment (aa 578 – 812) that was homologous to the putative catalytic region conserved among all mammalian PDEs and a segment (aa 142– 526) that was homologous to the putative cGMP binding region of PDE2 and of PDE6. The amino-terminal 142 residues showed no significant homology to other PDEs and contained a serine

(aa 92) that is phosphorylated by PKG. Human cG-BPDE (PDE5A) cDNA was isolated and characterized. PDE5A mRNA was shown to be expressed in aortic smooth muscle cells, heart, placenta, skeletal muscle, pancreas, and, to a much lesser extent, in the brain, liver, and lung (Loughney et al., 1998). Two 5V-splice variants, which possess distinct Nterminal sequences, PDE5A1 and PDE5A2, were identified (Kotera et al., 1998; Loughney et al., 1998), whose mRNA is differently tissue-distributed. Today, it was shown in human corpus cavernosum that only 1 gene PDE5A encodes 3 PDE5 isozymes from 2 alternate promoters that were up-regulated by increasing either cAMP or cGMP (Lin et al., 2002). The 3dimensional structure of native PDE5A and PDE6 resolved by electron microscopy/image analysis (Fig. 5) reveals a dimeric arrangement for PDE5 highly homologous with native PDE6, each subunit being organized into 3 distinct domains corresponding to the catalytic and 2 GAF domains. The major interaction between the 2 subunits is located at the N-terminal part. The interface between subunits delimitates a channel, which may provide a unique opportunity for the various effectors, such as cGMP, to interact with their functional sites (Kameni-Tcheudji et al., 2001). Modeling the GAF A domain of PDE5A on the crystal structure of PDE2A, GAF domain reveals that GAF A adopts a structure similar to the GAF B domain of PDE2A and provides the sole site for cGMP binding in PDE5A (Sopory et al., 2003). A comparison of the crystal structures of PDE4 and PDE5 in complexes with 3-isobutyl-1-methyl xanthine (IBMX), a nonspecific inhibitor, results in the subpocket characterization that may be a common site for binding nonselective inhibitor and reveals 3 regions for PDE5 having different conformation from PDE4 (Huai et al., 2004).

PDE5 C-terminal Catalytical Domain Repeat A Repeat B and N-terminus

PDE6 C-terminal Catalytical Domain Repeat A Repeat B and N-terminus Fig. 5. Three-dimensional structure of native human platelet PDE5 and of native bovine rod PDE6 obtained by electron microscopy and image analysis. Adapted from Kameni-Tcheudji et al. (2001).

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3.5.2. Short-term regulation cGMP binding, phosphorylation, and protein –protein interaction mediate short-term regulation of PDE5. The binding of cGMP to allosteric site of PDE5 was shown to be required for its phosphorylation (Turko et al., 1998), which increases PDE5 activity (Tremblay et al., 1985; Corbin et al., 2000), with an apparent conformational change and a 10-fold increase in cGMP binding affinity (Francis et al., 2002). However, it was clearly demonstrated that cGMP could also directly activate PDE5 without phosphorylation in response to sustained NO in the platelet (Mullershausen et al., 2003). This results from the binding of cGMP to the PDE5 GAF A domain, inducing a 9- to 11-fold reversible activation (Rybalkin et al., 2003). In opposite, it was shown that proteins, that are immunologically related to the gamma subunit of PDE6, which may exist in smooth muscle (Tate et al., 1998), regulate PDE5 by preventing PKA-mediated activation of PDE5 (Lochhead et al., 1997). Consequently, the PDE5 activation state is clearly dependent on cGMP intracellular level, which may regulate at least 3 different steps of activation: a basal low hydrolytic state in absence of cGMP; a reversible activated state when cGMP binds to GAF A, which is a prerequisite to allow phosphorylation; and a full activation of PDE5.

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3.5.5. Functional role PDE5 was firstly implicated in vasorelaxation, since the specific inhibition of PDE5 by zaprinast was shown to induce an increase in cGMP associated with a vasorelaxing effect (Lugnier et al., 1986; Schoeffter et al., 1987). The potentiation of a PDE5 inhibitor relaxing effect obtained on the aorta containing functional endothelium or treated with NO donors (Martin et al., 1986; Harris et al., 1989) suggested that PDE5 mediates the NO/cGMP relaxing effect (Rapoport & Murad, 1983). In that way, new PDE5 inhibitors derived from zaprinast were designed as antihypertensive compounds or coronary vasodilators; unexpectedly, during clinical studies, sildenafil ameliorated erectile dysfunction, pointing out PDE5 as a new target for treatment of erectile dysfunction and increasing the development of PDE5 inhibitors. The high level of PDE5 encountered in the lung, as well the observation that PDE5 was activated in pulmonary hypertension (Hanson et al., 1998b), has contributed to propose also PDE5 as a new target for the treatment of pulmonary hypertension and respiratory distress. Furthermore, in agreement with PDE5 characterization in the brain, it was recently shown that PDE5 inhibition improves early memory consolidation of object information (Prickaerts et al., 2004). 3.6. Phosphodiesterase 6 family

3.5.3. Long-term regulation During the regulation of pulmonary resistance, especially for perinatal development, it was shown that within 1 hr following birth, PDE5 activity, protein, and mRNA are decreased, whereas 4 to 7 days following birth, a secondary increase occurs, implying a complex regulation of PDE5 transcription, which may regulate pulmonary vascular resistance (Hanson et al., 1998a). In that way, PDE5 expression could be induced in a cAMP-dependent manner during murine neuroblastoma cell differentiation (Giordano et al., 1999). Furthermore, in corpus cavernous smooth muscle cells, sildenafil up-regulates PDE5 mRNA and protein (Lin et al., 2003). This is in agreement with the characterization of an intronic promoter that can be regulated by either cAMP or cGMP (Lin et al., 2001). 3.5.4. Distribution Western blot analysis in mouse tissues revealed the highest PDE5 expression in the lung, followed by the heart and cerebellum (localized in cerebellar Purkinje neurons), and lower signal in the brain and kidney (Giordano et al., 2001). PDE5 is expressed in rat pulmonary artery, which controls pulmonary resistance (Pauvert et al., 2003). PDE5 was recently shown to be expressed in isolated cardiomyocytes from dog, resolving the question concerning the hypothetical presence of PDE5 in the heart (Senzaki et al., 2001). A 85-kDa PDE5 is mainly expressed in human platelets and represent their major cGMP-PDE hydrolytic activity (Kameni-Tcheudji et al., 2001).

After showing that retinal PDE was the main site for light regulation of cyclic GMP metabolism (Goridis & Virmaux, 1974), the partial purification of this PDE reveals that bovine photoreceptor cGMP-PDE was allosterically regulated by cGMP, having an higher affinity for cGMP than for cAMP (Coquil et al., 1975). High purification of rod outer segments cGMP-PDE from retinal frog allowed to show that the enzyme has a heterodimeric structure (120 and 110 kDa), with a K m of 70 AM, and that 1 molecule of bleached rhodopsin activates 1 molecule of cGMP-PDE (Miki et al., 1975). A model for cGMP cascade in the retina was proposed (Chabre et al., 1988), in which photoactivated rhodopsin triggers a cascade of fast reactions mediated by transducin (G protein), which leads to the amplified activation of cGMP-PDE. Since this enzyme displayed a high specificity for cGMP, binding sites for cGMP, and a sensitivity to zaprinast similar to smooth muscle PDE5, both enzymes were named cGMP-PDE. However, retinal cGMPPDE, being specifically distributed in the retina, having a higher V max and K m values than other cGMP-PDEs and being regulated by G protein, was first distinguished as photoreceptor cGMP-PDE, or rod outer segments PDE, that is, ROS-PDE and, next, according to Beavo (1995) nomenclature named PDE6. 3.6.1. Structure Today, cloning and structural studies show that PDE6, which is a key component in the visual transduction cascade (Stryer, 1996), is composed of 2 large catalytic subunits (a

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and h in rods, 99 and 98 kDa, respectively; 2 aV in cones, 90 kDa each), 2 copies of inhibitory small subunits (rod g and cone gV, 11 and 13 kDa, respectively), and a 17 kDa y subunit (Gillespie & Beavo, 1989). Each of these subunits is the product of separate genes. Two noncatalytic cGMPbinding domains were identified as a conserved segment of 340 residues containing 2 repeats that are homologous to the allosteric sites for PDE2 (Charbonneau et al., 1990). Each g subunit interacts with at least 2 distinct sites on the catalytic subunit. The affinity of this interaction is regulated by cGMP binding to the GAF domains of PDE6 (Norton et al., 2000). The respective genes for the various subunits were cloned: PDE6A for rod a subunit (Ovchinnikov et al., 1987), PDE6B for rod h subunit (Lipkin et al., 1990), PDE6C for cone aV subunit (Li et al., 1990; Piriev et al., 1995), PDE6D for rod y subunit, which allows the solubilization of membrane-bound rod PDE6 (Florio et al., 1996; Li et al., 1998), PDE6G for the 11-kDa rod g subunit (Ovchinnikov et al., 1986), and PDE6H for the 13-kDa cone g subunit (Hamilton & Hurley, 1990; Shimizu-Matsumoto et al., 1996). The structure for membrane-bound rod PDE6 holoenzyme is ahg2 (Artemyev et al., 1996), whereas it is aV2g2 for cone PDE6. Recently, GAF A and GAF B domains were ascribed for frog PDE6 (Yamazaki et al., 2002) and for chicken cone PDE6 (Huang et al., 2004). GAF A domain may allow dimerization, binding of g subunit, and binding of cGMP that is required for high-affinity binding of g subunit (Muradov et al., 2004). The molecular organization of bovine rod PDE6 investigated by electron microscopy revealed a 3-dimensional dimeric ahy complex arrangement containing 3 distinct domains that correspond to the catalytic and 2 GAF domains (Kameni-Tcheudji et al., 2001). The comparison of the molecular organization of nonactivated PDE6 to activated PDE6 using electron microscopy suggests that the basic structure of PDE6 does not change during its regulation by g subunit (Kajimura et al., 2002). 3.6.2. Short-term regulation cGMP binding, phosphorylation, and protein interaction are requisite processes to allow cGMP visualling cascade. The cGMP binding to GAF domains is regulated by the binding of g and y subunits to ah PDE6 heterodimer (Mou et al., 1999). The g subunit, which switches the PDE6 hydrolytic activity, is light regulated by GTP-bound a subunit of transducin. Its phosphorylation by PKC may decrease PDE6 activation by transducin and, consequently, the photoresponse (Udovichenko et al., 1996). Furthermore, its phosphorylation by cyclin-dependent protein kinase 5 inhibits transducin-activated PDE6, even in the presence of transducin, contributing in the recovery phase of phototransduction (Hayashi et al., 2000). 3.6.3. Functional roles PDE6 plays a major role in phototransduction. The PDE6 cascade activation is initiated when the protein rhodopsin absorbs a photon. Each activated rhodopsin activates

thousands of transducin (a G-protein composed of 3 subunits: a, h, and g) by catalyzing the exchange of GDP for GTP. Transducin Ta subunit, with GTP bound, activates the catalytic PDEah subunits by displacing g subunits from the active site of the enzyme, thus allowing cGMP hydrolysis. The main function of the rod PDE is to rapidly reduce the steady-state concentration of cGMP in response to light stimulus. This decrease in cGMP concentration causes the closure of CNG cationic channels and generates cell membrane hyperpolarization. This initial signal is transmitted via second-order retinal neurons to the optic nerve and to the brain (Pugh & Lamb, 2000). Numerous visual alterations have been related to mutations affecting the various protein subunits of the rod and cone PDEs. More recently, another functional role was shown for PDE6 since, in chick pineal gland cells, rod and cone forms of PDE6 are expressed and play a role in the inhibition by light of melatonin synthesis (Morin et al., 2001). 3.7. Phosphodiesterase 7 family A cDNA was isolated from a human glioblastoma cDNA library and shown to encode a novel cAMP-specific PDE characterized by high affinity for cAMP (K m = 0.2 AM) and low V max, which does not share other properties of PDE3 and PDE4 (insensitivity to cGMP, milrinone, rolipram, and Ro 20-1724; Michaeli et al., 1993). According to the Beavo nomenclature, this new family, insensitive to rolipram, was designed as the PDE7 family (Beavo, 1995). Today, this family includes 2 genes encoding PDE7A and PDE7B. The PDE7 family does not contain GAF domains as well as regulatory domains. 3.7.1. Phosphodiesterase 7A Alternative splicing for PDE7A and the tissue-specific expression of PDE7 splice variants were identified (Bloom & Beavo, 1996; Han et al., 1997). The splices differ at the level of 5V for mouse (52.4 kDa) and human (50 kDa) skeletal muscle PDE7A2 and for human lymphocyte (55 kDa; Ichimura & Kase, 1993) and particulate skeletal muscle (57 kDa) PDE7A1 (Wang et al., 2000). Additionally, it was suggested that PDE7A might interact in the Golgi of T-lymphocyte with myeloid translocation gene (Asirvatham et al., 2004). PDE7A mRNA is ubiquitously distributed in human proinflammatory and immune cells (Smith et al., 2003), as well as in endothelial cells (Miro et al., 2000). PDE7A mRNA is widely distributed in the rat brain, in both neuronal and non-neuronal cell populations. In peripheral organs, the highest level of PDE7A mRNA was seen in kidney medulla, testis, liver, and adrenal glands (Miro et al., 2001). PDE7A1 protein was greatest in T-cell lines, peripheral blood T-lymphocytes, epithelial cell lines, airway and vascular smooth muscle cells, lung fibroblasts, and eosinophils but was not detected in neutrophils. In contrast, the PDE7A2 protein, identified in human cardiac myocytes,

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was not found in any of the other cell types investigated (Smith et al., 2003). PDE7A expressed in human Blymphocytes is up-regulated by cAMP (Lee et al., 2002a, 2002b). The functional promoter was characterized for PDE7A1, containing 3 CREB-binding sites, as well as binding site for other transcription factors Ets-2, nuclear factor of activated T-cells 1 (NFAT-1), and nuclear factor kappaB (NF-kappaB; Torras-Llort & Azorin, 2003). PDE7A1 and PDE7A3 were shown to be required for Tcell activation induced by the costimulation of CD3 and CD28 receptors, since increased PDE7 correlated with a decrease in cAMP, increased interleukin-2, and increased proliferation (Li et al., 1999; Glavas et al., 2001). Nevertheless, phosphodiesterase 7A-deficient mice have functional T-cells, supporting the notion that PDE7A is not essential for T-cell activation (Yang et al., 2003). 3.7.2. Phosphodiesterase 7B The cDNA of PDE7B was simultaneously identified by searching expressed sequence (EST) database derived from mouse mammary gland with the amino sequence of human PDE7A (Sasaki et al., 2000) and by cloning (Gardner et al., 2000). PDE7B mRNA was abundantly expressed in the brain and heart, followed by skeletal muscle and pancreas. The deduced amino acid sequence of human PDE7B was 64% identical to that of human PDE7A. Recombinant PDE7B (53 kDa) has the same K m value as PDE7A (0.13 and 0.16 AM, respectively), and V max value is 1/2 to 1/3 of recombinant human PDE7A (Sasaki et al., 2000). PDE7B2 and PDE7B3 were identified as novel splice variants of rat PDE7B, and 2 phosphorylation sites for PKA were found for PDE7B1 and PDE7B3, whereas rat PDE7B2 possessed 1 site; this, later on, was a testis-specific PDE7B variant (Sasaki et al., 2002). PDE7B1, but not other splice variants, was activated by D1 agonist through the cAMP/cAMPdependent protein kinase –cAMP-response element binding protein pathway in striatal neurons, arguing a role for PDE7B1 in memory function (Sasaki et al., 2004). 3.8. Phosphodiesterase 8 family 3.8.1. Phosphodiesterase 8A A high-affinity, cAMP-specific PDE (K m = 0.15 AM), insensitive to rolipram and IBMX, named PDE8A, was cloned from human (Fisher et al., 1998a) and from mouse testis (Soderling et al., 1998a, 1998b). PDE8 mRNA has highest the expression in the testis, followed by the eye, liver, skeletal muscle, heart, kidney, ovary, and brain, in decreasing order. This PDE contains an Nterminus that is homologous to the PAS domain found in many signal transduction proteins (Soderling et al., 1998a, 1998b). PDE8As 1– 5 splice variants of PDE8A were cloned from testis, T-cells showing various distributions of PAS domains, and a receiver (REC) domain for human PDE8A1 (93 kDa) and PDE8A (88.3 kDa). In all tissues, the expression levels of PDE8A1 are much

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higher than that of PDE8As 2 – 5 (Wang et al., 2001). PDE8A1 is induced in response to a combination of Tcell receptor and costimulatory receptor pathway activation (Glavas et al., 2001). 3.8.2. Phosphodiesterase 8B A second gene in the PDE8 family was discovered through a search of EST data base, encoding PDE8B, and showing 65% of identity to that of PDE8A. The mRNA encoding PDE8B is expressed specifically and abundantly in the thyroid gland (Hayashi et al., 1998). The recombinant PDE8B, like PDE8A, is insensitive to IBMX, rolipram, and milrinone, but is 3-fold less sensitive to dipyridamole and more sensitive to PDE5 inhibitors and to erythro-9-(2hydroxy-3-nonyl)adenine (EHNA). There are at least 4 PDE8B variants: PDE8B1 (K m = 101 nM, 105 kDa), as well as PDE8B4 contains an N-terminal REC domain, a PAS domain, and a C-terminal catalytic domain, whereas both PDE8B2 and PDE8B3 have a deletion in the PAS domain. Three putative cAMP- and cGMP-dependent protein kinase phosphorylation sites are located between the PAS domain and the catalytic domain. RT-PCR analysis revealed that while PDE8B1 is the most abundant variant in the thyroid gland, PDE8B3 is the most abundant form in the brain (Hayashi et al., 2002). Mouse PDE8B1 protein is 99% and 96% identical to rat and human PDE8B1, respectively (Kobayashi et al., 2003). 3.9. Phosphodiesterase 9 In 1998, Beavo’s and Cheng’s teams independently and simultaneously identified PDE9 using either bioinformactic approach for mouse PDE9A1 (Soderling et al., 1998a, 1998b) or sequence homology for human PDE9A (Fisher et al., 1998b). Recombinant PDE9A1 (62 kDa) is highly specific for cGMP (K m = 0.07 AM, 40 –170 times lower than that of PDE5 and PDE6, respectively) and is insensitive to IBMX or sildenafil, but is inhibited by the PDE1/PDE5 inhibitor, SCH51866, with an IC50 of 1.55 AM. PDE9A1 mRNA is highly distributed in the kidney and to lower levels in the liver, lung, and brain (Soderling et al., 1998a, 1998b). Similarly, human PDE9A mRNA is expressed in the spleen, small intestine, and brain. Recombinant PDE9A has a K m of 170 nM for cGMP and 230 AM for cAMP. The V max for cGMP is about twice as fast as that of PDE4 for cAMP. PDE9A is insensitive to rolipram and IBMX but is inhibited by zaprinast (IC50 = 35 AM; Fisher et al., 1998b). The murine and human PDE9A cDNAs share 93.5% amino acid identity in the catalytic domain, and the putative regulatory domain of PDE9A does not contain a GAF domain. The alternative splicing of mRNA transcripts was characterized (PDE9As1 –4; Guipponi et al., 1998). The pattern of PDE9A mRNA expression in the brain closely resembles that of soluble guanylyl cyclase, suggesting a possible functional association in the regulation of cGMP levels that may play an important role in behavioral state

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regulation and learning (Andreeva et al., 2001). In that way, it was shown that PDE9 mRNA is highly conserved between species and is widely distributed throughout the rodent brain, and it was suggested that PDE9 is present in Purkinje cells (Van Staveren et al., 2002). DNA microarray studies reveal that in preconditioned rat heart, where NO regulation was implicated, there is an increase in PDE9A1 (Onody et al., 2003). A new human splice variant, PD9A5, highly expressed in immune tissues and being exclusively in the cytoplasm, was characterized, whereas PDE9A1 localized in the nucleus only (Wang et al., 2003). More than 20 variants have been observed, indicating that the PDE9A gene appears to have a complex regulation of expression (Rentero et al., 2003). The crystal structure of the catalytic domain of PDE9A2 reveals that IBMX binds in a similar subpocket in the active site of PDE4 and PDE5, however, it significantly differs by its orientation (Huai et al., 2004). Also, this study surprisingly reveals that the catalytic domain of PDE9A2 is closer to PDE4D2 than to PDE5A1. Until now, very few studies revealing PDE9 protein tissue distribution were done, as well as investigations about their functional implication. Their specific subcellular distribution argues for a major role in compartmentation that needs to be investigated. 3.10. Phosphodiesterase 10 The PDE10 family was isolated and characterized as a dual-substrate gene family in 1999 from mouse (Soderling et al., 1999) as well as from human fetal lung (Fujishige et al., 1999) and fetal brain (Loughney et al., 1999). The deduced amino acid sequence contains 779 aa and includes 2 GAF domains in the N-terminal fraction. A study on genomic organization reveals that despite containing 2 GAF domains, PDE10A has a different gene organization from PDE5A and PDE6B (both containing GAF domains) and suggests that the ancestral gene for PDE10A existed in a lower organism such as C. elegans (Fujishige et al., 2000). PDE10A hydrolyzes cAMP with a K m of 0.05 – 0.26 AM and cGMP with a K m of 3 –7.2 AM. Although PDE10A has a lower K m for cAMP, the V max ratio cGMP/cAMP is 2 – 4.7. Because of these kinetics, cGMP hydrolysis by PDE10 is potently inhibited by cAMP. PDE10A is mostly inhibited by dipyridamole (IC50 = 1 AM) and inhibited by IBMX (IC 50 = 3 – 17 AM) and zaprinast (IC 50 = 11 – 22 AM). PDE10A transcripts are particularly abundant in the brain (putamen and caudate nucleus), thyroid, and testis. PDE10A2, a novel alternative splice variant of human PDE10A, having a putative phosphorylation site by PKA, was characterized as a major form in human tissues. Although the recombinant PDE10A1 protein is not phosphorylated, recombinant PDE10A2 is preferentially phosphorylated by PKA in its unique-N terminus, opening a new regulation way of its potential physiological roles, especially in the striatum (Kotera et al., 1999). PDE10A2 is more abundant in membrane fractions than in cytosolic

fractions of rat striatum, and immunocytochemical analysis showed that PDE10A2 (87 kDa) is localized in the Golgi apparatus of transfected cells. It was also suggested, by mutation study, that PKA causes alteration of subcellular localization of PDE10A2 from the Golgi apparatus to cytosol (Kotera et al., 2004). Various alternative splices variants have been implicated in long-term potentiation (LTP), such as PDE10A3/A6 and PDE10A5/A11, which are up-regulated following the induction of LTP, reducing cGMP elevation (O’Connor et al., 2004). This PDE family was recently shown to be associated to the progressive neurodegenerative disease Huntington’s disease (HD), since PDE10A2 mRNA decreases prior to the onset of motor symptoms in transgenic HD mice expressing exon 1 of the human huntingtin gene (Hebb et al., 2004; Hu et al., 2004). These first data showing that PDE10A seems to be implicated in neuropathophysiology do not exclude the possible role of PDE10A in other tissues such as thyroid, kidney, and testis. 3.11. Phosphodiesterase 11 The PDE11 family represents a dual-substrate PDE family having a catalytic site most similar to PDE5 (50% identity and 71% similarity) than to PDE10A (41% identity and 64% similarity; Fawcett et al., 2000). PDE11 mRNA occurs at higher levels in skeletal muscle, prostate, kidney, liver, pituitary and salivary glands, and testis. PDE11A1 (491 aa) was cloned from human skeletal muscle and predicted to have a molecular mass of 55,786 Da and contained only 1 GAF domain. Western blotting of human tissue distinguishes 3 proteins of 78, 66, and 56 kDa. Recombinant PDE11A1 hydrolyzes cGMP and cAMP with K m values of 0.52 and 1.04 AM, respectively, with similar V max values. PDE11A is sensitive to IBMX (IC50 = 50 AM), zaprirnast (IC50 = 12 AM), and dipyridamole (IC50 = 0.37 AM). The 66-kDa protein was characterized (Hetman et al., 2000) as PDE11A2 (576 aa; 65.8 kDa) and the 56-kDa protein as a PDE11A3 (684 aa; 78.1 kDa). Two splice variants were characterized: PDE11A3 (684 aa; 78 kDa), which contains 1 complete and 1 incomplete GAF domain in the N-terminal region; and PDE11A4 (934 aa; 100 kDa), which includes 2 complete GAF domains and a putative phosphorylation site for PKA and PKG (Yuasa et al., 2000). PDE11A3 transcripts are specifically expressed in the testis, whereas PDE11A4 transcripts are particularly abundant in the prostate. The inhibitory effects of PDE inhibitors on HPDE11A3 activity were 2- to 3-fold more potent than those on HPDE11A4 (Yuasa et al., 2000). However, these differences were not observed between rat PDE11A splicing variants, whose tissue distribution differs from human PDE11A distribution, indicating that rat is not a good animal model for investigating the physiological function of PDE11A (Yuasa et al., 2001). The PDE11A gene, which undergoes tissue-specific alternative splicing that generates structurally and functionally distinct genes

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products, may have tissue-selective functions that remain to be elucidated.

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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 more or less selective and potent PDE inhibitors have been synthetized and developed by academic research and pharmaceutical companies. Some of them inhibit PDE activity very potently in nanomolar and subnanomolar range and are very specific for 1 family. Thus, in the span of 40 years, the potency of PDE inhibitors has increased by 108, and the specificity of some of them by 104. PDE inhibitors were and are now mainly used as a pharmacological tool to characterize PDE isozymes in tissues and cells as well as to characterize the functional role of PDEs and their implication in pathophysiological states.

firstly described as a calmodulin-activated PDE inhibitor (Bergstrand et al., 1977); however, the isolation of PDE5 from PDE1 in calmodulin-activated fraction allowed to show unequivocally that, in fact, zaprinast is specific for PDE5, inhibiting PDE1 at higher concentration (Lugnier et al., 1986). Compound SCH 51866 is used as PDE1 inhibitor (according to gene and splices, IC50 vary from 13 to 100 AM, Yan et al., 1996); however it inhibits PDE1 and PDE5 with same potency (IC50 of 70 and 60 nM, respectively; Vemulapalli et al., 1996). Furthermore, SCH 51866 inhibits also the new PDE isozymes: PDE7B (IC50 = 1.5 AM; Sasaki et al., 2000), PDE9A (IC50 = 1.55 AM; Soderling et al., 1998a, 1998b), PDE11A3, and PDE11A4 (IC50 = 9 to 25 AM; Yuasa et al., 2000). The compound 8-methoxymethyl IBMX, sold as PDE1 inhibitor by biochemical companies, is also a poor selective inhibitor of PDE1, since it also inhibits PDE5 in the same range (IC50 = 8 and 10 AM, respectively; Ahn et al., 1997). Recently, a new PDE1 inhibitor, IC224 (IC50 = 0.08 AM), with a selectivity ratio of 127 (ratio of IC50 value for the next most sensitive PDE and for IC50 value for PDE1), was developed by ICOS Corporation (Snyder et al., 2005). According to these few data, if IC224 similarly inhibits basal and calmodulin-activated PDE1 subtypes, this compound would be very helpful to characterize PDE1 activity and to clearly investigate the various roles of PDE1 in pathophysiology.

4.1. Phosphodiesterase 1 inhibitors

4.2. Phosphodiesterase 2 inhibitors

Nimodipine, a dihydropyridine that antagonizes specifically L-type Ca channel, was firstly described as a CaMPDE inhibitor (Epstein et al., 1982), This effect is not related to its calcium antagonist property since it inhibits, in micromolar range, basal and calmodulin stimulated purified PDE1 (Lugnier et al., 1984). Since nimodipine at lower concentrations blocks the L-type calcium channel, it can only be used to estimate PDE1 participation in tissue and cell homogenates (Georget et al., 2003). Today, there is no real and effective specific PDE1 inhibitor that can be used to assess the functional role of PDE1 in tissue. Vinpocetine was described as a specific inhibitor of basal and calmodulin-activated PDE1 (Hagiwara et al., 1984) and mainly used as a pharmacological tool to implicate PDE1. It must be pointed out that this compound inhibits differently the various subtypes of PDE1 (IC50 from 8 to 50 AM; Yan et al., 1996) and that it is also able to inhibit PDE7B with an IC50 of 60 AM (Sasaki et al., 2000). Furthermore, due to its direct activator effect on BK (Ca) channels (Wu et al., 2001), it could not be used as a specific tool to investigate the functional role of PDE1. In another way, many compounds reported as PDE1 inhibitor do not interact directly with the catalytic site of PDE1 but interact during activation, either at the level of calmodulin binding sites such as compound KS505a (Ichimura et al., 1996) or directly on Ca/calmodulin such as bepril, flunarizine, and amiodarone (Lugnier et al., 1984; Nokin et al., 1989). Zaprinast (M&B 22948) was

Until 1994, no specific inhibitor of PDE2 was known; therefore, some compounds were chosen to investigate PDE2 function in specific condition. For instance, we used cilostamide, a PDE3 selective inhibitor, as cGMP-stimulated PDE2 inhibitor in bovine aortic endothelial cells that are devoided of PDE3 (Kessler & Lugnier, 1995). EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), previously known as MEP 1 (Podzuweit et al., 1992), was shown to specifically act on PDE2 by inhibiting cGMP-activated PDE2 with an IC50 value of 3 AM (Podzuweit et al., 1995). The precise mechanism of this inhibition is not entirely elucidated, since EHNA does not appear to displace cGMP from the regulatory site on PDE2 (Mery et al., 1995). However, at lower concentrations, EHNA inhibits adenosine deaminase (K i = 10 9 M). Therefore, it must be used with caution as a PDE2 inhibitor; for instance, 2V-deoxycoformycin (1 –30 AM), another adenosine deaminase inhibitor with no effect on PDE2, can be used to check the possible implication of adenosine deaminase. EHNA was used to study the implication of PDE2 in calcium control in cardiac myocytes (Rivet-Bastide et al., 1997) and was shown effective to reverse hypoxic pulmonary vasoconstriction in perfused rat lung model (Haynes et al., 1996). Many compounds significantly interfere with PDE2, such as dipyridamole, trequinsin, cilostamide (Lugnier & Komas, 1993; Stoclet et al., 1995), as well as chelerytrine, sold and used as a PKC inhibitor (Eckly-Michel et al., 1997a). Some

4. Specific inhibitors of the phosphodiesterase families

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of them have complex effects on PDE2, acting similarly to cGMP: At a low concentration, they activate PDE2 and, at higher concentration, inhibit PDE2. This effect depends also on the cAMP concentration used in the assay (Yamamoto et al., 1983; Lugnier & Schini, 1990; Komas et al., 1991a). Recently, 2 new PDE2 inhibitors were reported: IC933, with an IC50 value of 0.004 AM and a 235 selectivity ratio (Snyder et al., 2005); and Bay 60-7550, which increases neuronal cGMP, synaptic plasticity, and memory performance (Boess et al., 2004). These 2 inhibitors will open PDE2 research field and the discovery of new therapeutic targets, as much as TNFa is able to up-regulate PDE2 in endothelial cells, destabilizing endothelial barrier function in sepsis, indicating that PDE2 inhibitor will be of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS, Seybold et al., 2005).

inhibit PDE3A with a 2-fold more potency than PDE3B and led to the design of a cilostamide analogue, OPC-33540, which preferentially inhibits PDE3A (PDE3A IC50 = 0.32 nM, PDE3B IC50 = 1.5 nM; Sudo et al., 2000). Recently, dihydropyridazinone was conceived by Merck and Co as the first orally active, potent, and selective PDE3B (PDE3B IC50 = 0.19 nM, 3A IC50 = 1.3 nM; Edmondson et al., 2003). These relative selective subtype PDE3 inhibitors open the possibility to conceive more specific PDE3 subtype devoided of interactions with other family; they also represent new pharmacological tools that will allow to discriminate the respective functions of PDE3A (mainly implicated in cardiovascular function and fertility) and of PDE3B (mainly implicated in lipolysis).

4.3. Phosphodiesterase 3 inhibitors

Rolipram (ZK 62711, Schering AG), an antidepressant compound (Schwabe et al., 1976), was shown to be a potent cAMP-PDE inhibitor in brain homogenates. The high selectivity of rolipram, as well as of Ro 20-1724, for PDE4 was demonstrated on vascular purified PDE (Lugnier et al., 1983, 1986; Komas et al., 1989). Therefore, PDE4 became an archetype to synthetize new potent and selective PDE4 inhibitors (Marivet et al., 1989). Denbufylline, a xanthine derivative, is also selective for PDE4, but inhibits PDE5 at 10-fold higher concentration (Lugnier & Komas, 1993). Since PDE4 was characterized as a new target to design anti-inflammatory drugs (Torphy & Undem, 1991; Manning et al., 1999), many pharmaceutical companies started to develop rolipram analogues for asthma and COPD, such as Piclamilast (Rhoˆne-Poulenc Rorer, RP7034; Souness et al., 1995), CDP-840 (Celltech Therapeutics limited and Merck Frosst, IC50 = 2 – 30 nM; Perry et al., 1998), and its derivative L-791,943 (Alexander et al., 2002; Guay et al., 2002). However, these rolipram analogues, due to their adverse emetic effect, failed in clinical studies. Also, other chemical structures were used to search new classes of PDE4 inhibitors. Benzyladenine derivatives (Bourguignon et al., 1997, Raboisson et al., 2003) were synthetized as potent and selective inhibitors being effective in vivo per oral administration (NCS613, IC50 = 42 nM, Boichot et al., 2000; NCS 706, IC50 = 0.1 nM, Reimund et al., 2001). Presently, some new PDE4 inhibitors, with lesser emetic effects, are currently under clinical investigation, such as cilomilast (Ariflo; SB 207499, GlaxoSmithKline, IC50 = 95 nM; Christensen et al., 1998), roflumilast (Daxas\, Altana, IC50 = 0.8 nM; Hatzelmann & Schudt, 2001), SCH 351591 (IC50 = 58 nM; Billah et al., 2002), V11294A (IC50 = 405 nM; Gale et al., 2002), AWD 12-281 (elbion AG, IC50 = 9.7 nM; Draheim et al., 2004). Furthermore, compound L826,141 from Merck slightly discriminates PDE4 subtypes (IC50 = 0.26 to 2.4 nM for catalytic domain activity of PDE4A, B, C, and D; Claveau et al., 2004). Besides that PDE4 inhibitors are new anti-inflammatory drugs in asthma and COPD, as well as new antidepressant

Cilostamide (OPC-3689; Hidaka et al., 1979) was described as the first potent selective inhibitor of cAMPPDE in the platelet. The comparison of its effects on cAMPPDE isolated from platelets and from vascular smooth muscle, as well as its relaxant and antiaggregatory effect, pointed out the specificity of cilostamide for platelet cAMPPDE (which was later identified as PDE3), indicating that platelet cAMP-PDE differed from vascular smooth muscle cAMP-PDE (Lugnier et al., 1983). PDE3 inhibitors have been extensively investigated during the 1980s and 1990s. Some of them were initially developed as new nonglycoside, non-sympathomimetic, cardiotonic agent for the treatment of heart failure (Bristol et al., 1984; Moos et al., 1987). However, due to their arrythmogenic properties, pharmaceutical company interest in developing PDE3 inhibitors in heart failure was stopped. Milrinone has been the most studied and used extensively as PDE3 inhibitor, and it is currently used in the acute treatment of heart failure to diminish long-term risks (Cruickshank, 1993). Milrinone (Primacor\) is about 25-fold more potent than its related compound amrinone, but it also inhibits PDE4 and PDE5 at about 10-fold higher concentrations (Lugnier & Komas, 1993). Enoximone, piroximone, CI-930, sulmazole, pimobendan, and its metabolite UD-CG 212 CL all inhibit PDE3 at concentrations ranging from 10 7 to 10 5 M, but as for milrinone, these compounds also inhibit PDE4 and PDE5 at higher concentrations (Brunkhorst et al., 1989; Komas et al., 1989; Stoclet et al., 1995). Trequinsin (HL 725; Ruppert & Weithmann, 1982) inhibits PDE3 in the nanomolar range; however, it also potently inhibits PDE1, PDE2, and PDE4 at submicromolar concentrations (Stoclet et al., 1995). Cilostazol (Pletal\), a dual inhibitor of PDE3 and adenosine uptake, due to its antiaggregant and vasodilator properties, is presently on the pharmaceutical market for the treatment of intermittent claudication (Liu et al., 2001a, 2001b). The investigation of PDE3 inhibitor effects towards PDE3 subtypes showed that cilostamide, cilostazol, and amrinone

4.4. Phosphodiesterase 4 inhibitors

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drugs, a growing number of studies performed with PDE4 inhibitors open new therapeutic area. In the inflammatory pathology field, PDE4 inhibition decreases the expression of mucin gene in human airway epithelial cells (Mata et al., 2005) and reduces the parainfluenza 3-virus induced airway influx of macrophages, eosinophils, and neutrophils (Toward et al., 2005). In central nervous system, rolipram treatment improves deficits in both long-term potentiation (LTP) and contextual learning in the double transgenic mice for amyloid precursor protein, suggesting that PDE4 inhibitor would be effective in Alzheimer disease (Gong et al., 2004). Furthermore, PDE4 inhibition will be a new approach for schizophrenia (Maxwell et al., 2004) and defective long-term memory such as Rubinstein-Taybi syndrome (Bourtchouladze et al., 2003). Rolipram promotes axonal regeneration and functional recovery (Nikulina et al., 2004), stimulates osteoclast formation (Waki et al., 1999; Takami et al., 2005), activates mitochondrial apoptosis in chronic lymphocytic leukemia cells (Moon & Lerner, 2003), and inhibits HIV-1 replication in cultures stimulated by antiCD3/CD28 T Tat (Secchiero et al., 2000). Specific PDE4A4 subtype inhibitor would be relevant as an anti-inflammatory target for COPD, since overexpressions of PDE4A4 were found in peripheral blood monocytes of smokers (Barber et al., 2004). These data point out that another generation of PDE4 inhibitors targeting specifically PDE splice variants would be relevant for specific pathology with minimal adverse effects. 4.5. Phosphodiesterase 5 inhibitors As reported previously in Section 3.1, zaprinast is the first characterized selective PDE5 inhibitor (Lugnier et al., 1986). MY-5445 was also shown to inhibit PDE5 (K i = 1.3 AM; Souness et al., 1989). Dipyridamole, for a long period, was referred and used as a specific inhibitor of PDE5. However, it interacts significantly with activated PDE2 and also with PDE4 (K i values of 1.9 and 2 AM, respectively; Lugnier & Komas, 1993), and more recently, it was shown to interact with the new PDE families PDE7, PDE8, and PDE11. Since zaprinast is a vasorelaxant compound, its chemical structure was used to conceive more potent and selective compounds (100- to 1000-fold more potent than zaprinast) as coronary vasodilator, such as (1,3-dimethyl-6(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3, 4d]-pyrimidin-4-(5H)-one) (DMPPO), a Glaxo compound, with a K i value of 3 nM (Coste & Grondin, 1995). This orally active compound was shown to be effective during chronic hypoxic pulmonary hypertension in rats (Eddahibi et al., 1998). Compound E4021, a specific and potent PDE5 inhibitor (K i = 2.4 nM; Miyahara et al., 1995; Saeki et al., 1995), was also shown to improve pulmonary hypertensive rats (Yamaguchi et al., 1998). Surprisingly and interestingly, clinical study reveals that 1 compound, sildenafil, would be beneficial for male erectile dysfunction (ED), and therefore, sildenafil was developed and marketed as Viagrai by

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Pfizer (IC50 = 3.9 nM; Boolell et al., 1996). However, similarly to DMPPO, this compound inhibits the retinal PDE6 with the same potency, inducing some blue tinting of vision (Gresser & Gleiter, 2002). Consequently, many companies designed other selective PDE5 inhibitors having lesser inhibitory effect towards PDE6. Presently, 3 PDE5 inhibitors are on the market for erectile dysfunction: sildenafil (Viagrai, Pfizer Inc.), vardenafil (Levitrai, Bayer-GSK), and tadalafil (Cialisi, IC351, Lilly-ICOS), which is 1000-fold less potent towards PDE6 (GF196960, GlaxoSmithKline, IC50 = 5 nM; Daugan et al., 2003). These compounds also interact with PDE11, with tadalafil being the most potent of them, with an IC50 = 73 nM, and vardenafil the less potent, with an IC50 = 840 nM (Weeks et al., 2005). Sildenafil was shown to induce neurogenesis and promote functional recovery after stroke in rat (Zhang et al., 2002a, 2002b), to be effective in hypoxia-induced pulmonary hypertension in rat (Sebkhi et al., 2003), and to improve endothelium-dependent vasodilatation in smokers (Kimura et al., 2003). Furthermore, as indicated previously, sildenafil and vardenafil enhance early memory consolidation of object information (Prickaerts et al., 2004). Vardafenil and tadalafil, PDE5/6 inhibitors, are able to induce caspase-dependent apoptosis in B-chronic lymphocytic leukemia cells (Sarfati et al., 2003). The 3 PDE5 inhibitors currently given for ED in human represent safe pharmacological tools to investigate the potential therapeutic effects of PDE5 inhibitors and to elucidate the intracellular signaling role of PDE5 in physiopathologies. 4.6. Phosphodiesterase 6 inhibitors PDE5 and PDE6, being structurally related, compounds inhibiting PDE5 also interact with PDE6 (Cote, 2004). Zaprinast and dipyridamole (K i = 140 and 380 nM, respectively; Gillespie & Beavo, 1989), as well as E4021, inhibit PDE6 as potently as PDE5 (D’Amours et al., 1999). Due to the adverse vision effects of PDE6 inhibitors and the specific localization of PDE6, in the retina, there is no pharmaceutical investment on PDE6 inhibitors. 4.7. Phosphodiesterase 7/8/9/10/11 inhibitors There are very few selective inhibitors known for these new families discovered by cloning, since their design is only beginning. IC242 inhibits PDE7A selectively, with an IC50 of 0.37 AM (Lee et al., 2002a, 2002b). Recently, BRL 50481 was discovered as a PDE7 inhibitor (K i = 180 nM), with an acceptable in vitro selectivity (Smith et al., 2004). Thiadiazoles, a new structural class of potent and selective PDE7 inhibitors, acting in the nanomolar range, was found by Pfizer (Vergne et al., 2004). For the last PDE families, only their differential sensitivity to known inhibitors was reported. PDE8A, insensitive to IBMX, is inhibited by dipyridamole, with an IC50 = 9 AM (Fisher et al., 1998a).

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PDE9A is only sensitive to zaprinast (IC50 = 35 AM; Fisher et al., 1998b). PDE10A is also inhibited by dipyridamole, with IC50 values of 1.2 and 0.45 AM for the inhibition of cAMP and cGMP hydrolysis (Fujishige et al., 1999). PDE11A variants are sensitive to dipyridamole, with an IC50 = 0.8 to 1.8 AM, and to zaprinast, with an IC50 = 5 to 28 AM (Hetman et al., 2000). There is no doubt that, in the near future, selective PDE inhibitors for PDE8 to 11 will be discovered, allowing to get insight in the knowledge of the functional role and potential therapeutic effects of these new PDEs.

5. 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. 5.1. Phosphodiesterase role in cardiac contraction In cardiac muscle, cAMP is the intracellular second messenger mediating the positive inotropic effects of hagonists (Tsien, 1977). PDE3 appeared to be the molecular target for PDE inhibitors described as ‘‘new cardiotonic drugs’’ such as amrinone, milrinone, piroximone, SK&F 94120, imazodan, or CI 930 (Harrison et al., 1986; Weishaar et al., 1987; Komas et al., 1989). The implication of cAMP in the positive inotropic effect of PDE3 was shown on guinea pig isolated left atria, since PDE3 inhibitors decrease the EC50 value of isoproterenol and their inotropic effects were enhanced by forskolin (Muller et al., 1990b). Furthermore, this study also clearly showed that cGMP acts in an opposite manner on cardiac contraction, since 8-Br-cGMP increases the EC50 value of isoproterenol and decreases PDE3 inhibitor inotropic effects. This is in agreement with the opposite effects of cAMP and cGMP reported on Ca2+ current in single heart cells (Hartzell & F1ischmeister, 1986). Further characterization of PDE4 and PDE2 in guinea pig and dog cardiac ventricles, as well as in frog atrial fibers and ventricles (Reeves et al., 1987; Komas et al., 1989; Lugnier et al., 1992; Muller et al., 1992), raised the question about their functional roles in the heart, in respect with to PDE3. A study performed with rolipram, denbufylline, and Ro 20-1724 as PDE4 inhibitors showed that, in contrast to PDE3 inhibitors, these PDE4 inhibitors did not produce any positive inotropic in normal or elevated external calcium concentration. But, in the presence of low concentrations of forskolin or a PDE3 inhibitor, all exerted concentration-dependent positive inotropic effects, suggesting that PDE4 may play a role in the regulation of cardiac contraction in physiological conditions

in which the sympathetic outflow produces a stimulation of adenylyl cyclase in cardiac cells (Muller et al., 1990a). Interestingly, ( ) rolipram was 10-fold more potent than the (+) enantiomer as positive inotropic agent, in agreement with its 20-fold higher affinity for specific binding to rat brain cAMP-PDE (Schneider et al., 1986). Biochemical characterization of cardiac isolated subcellular fractions revealed that PDE4 is preferentially associated to sarcolemma, whereas PDE3 is enriched in sarcoplasmic reticulum and that PDE2 is mainly associated to sarcolemma (Lugnier et al., 1993; Okruhlicova et al., 1998). These differential distributions of PDE4, PDE3, and PDE2 suggest a possible role of PDEs in the reported control of various cAMP compartments having a subcellular basis within the cardiomyocyte (Buxton & Brunton, 1983). The participation of PDEs in compartmentation was therefore shown in frog cardiac myocytes by using IBMX, a nonselective PDE inhibitor (Jurevicius & Fischmeister, 1996). Recent studies, performed by using a transfected cyclic nucleotide-gated channel sensitive to cAMP, demonstrated that PDE4, preferentially to PDE3, controls subsarcolemmal cAMP level (Rochais et al., 2004) and that its activity was increased consequently to h-stimulation. Furthermore, in transgenic mice, cardiac expression of AC8 is accompanied by a rearrangement of PDE isozymes (increase in PDE4 and decrease in PDE2), leading to a strong compartmentation of the cAMP signal that shields L-type Ca2+ channels and protects the cardiomyocytes from Ca2+ overload (Georget et al., 2003). Altogether, data concerning the localized role of PDE4 in the control of cAMP level and calcium regulation are in accordance with the positive inotropic effects reported for PDE4 inhibitors consequently to adenylyl cyclase stimulation (Muller et al., 1990a). The use of EHNA reveals the regulation of basal calcium current by PDE2 in cardiac myocytes (Rivet-Bastide et al., 1997). Furthermore, in cardiac myocytes, cGMP, like NO, was shown to act in an opposite manner on Ca2+ level. At low concentration, cGMP, by inhibiting PDE3, increases Ca2+ level, whereas at higher concentration, cGMP, by stimulating PDE2, decreases Ca2+ level, indicating a concerted regulation of PDE2 and PDE3 (Fig. 6; Vandecasteele et al., 2001). 5.2. Phosphodiesterase role in vascular contraction The role of PDE in vascular contraction was first reported when Kukovetz and Poch (1970) showed that the vasodilator papaverine inhibits cAMP-PDE in the vessel. This study was extent to papaverine analogues, showing a correlation between potencies of their vasodilatatory effects and their inhibitory effects toward vascular cAMP-PDE (Lugnier et al., 1972). Separations of PDE isoforms from human, bovine, and rat aorta allowed to characterize PDE1, PDE4, and PDE5, as well as the specific inhibitors rolipram (PDE4) and zaprinast (PDE5; Lugnier et al., 1986). The characterization of PDE3 in the aorta, together with PDE4 (Komas et al., 1991b), questioned about their respective role

C. Lugnier / Pharmacology & Therapeutics 109 (2006) 366 – 398

EHNA 5 µM cGMP

PDE2

NO 0.5 µM cGMP

cAMP

Ca2+

PDE3 cilostamide

Fig. 6. Biphasic NO/cGMP-dependent regulation of intracellular calcium in human cardiac myocytes mediated by PDE2 and PDE3. NO, by stimulating soluble guanylyl cyclase, dose-dependently increases intracellular cGMP levels. At a low concentration, cGMP inhibits PDE3 (as does cilostamide) and consequently increases cAMP levels, inducing a PKA-mediated elevation of intracellular calcium. At high concentrations, cGMP activates PDE2 and consequently decreases cAMP levels, reducing intracellular calcium. EHNA fully reverses the effect of high cGMP level. Adapted from Vandecasteele et al. (2001).

in vascular contraction. A relaxation study performed on precontracted aorta, with and without endothelium, with specific PDE3 and PDE4 inhibitors in combination with NO modulator demonstrates that PDE3 inhibitors are endothelium-independent vasorelaxant, whereas PDE4 inhibitors are endothelium dependent. Furthermore, NO donor, functional endothelium, or PDE3 inhibitor reveals the vasorelaxing effect of PDE4 inhibitor, indicating that cGMP elevation, consequently to NO-induced guanylyl activation, inhibits PDE3 and therefore increases cAMP level, allowing PDE4 to control cAMP level (Komas et al., 1991b; Eckly & Lugnier, 1994). This firstly showed a cross-talk between PDE3 and PDE4 mediated by cGMP (Fig. 7). To go further, a study was performed to investigate the participation of protein kinases in vascular contraction. Contrary to isoprenaline-induced relaxation mediated by PKA, the results obtained with PDE3 and PDE4 inhibitors showed that (i) relaxation induced either by PDE3 or PDE4 inhibitor alone is mediated by protein kinase G (PKG) despite that they only increase cAMP level; (ii) contrary to isprenaline, rolipram inhibits the ATP-induced transient increase in [Ca2+]I; and (iii) this inhibition is only mediated by PKG (Eckly-Michel et al., 1997b). This inhibitory effect of rolipram on [Ca2+]I is in agreement with PDE4 localization on sarcolemma. This reveals a cross-activation of PKG by cAMP in rat aorta, due to a localized increase in cAMP, as much as the relaxing effect of isoprenaline (0.01 to 0.3 AM) is only mediated by PKA. Furthermore, the combination of PDE3 and PDE4 inhibitors, which induces a higher increase in cAMP level in rat aorta (Eckly & Lugnier, 1994), is mediated by PKA (shown by an increased PKA activity ratio and by PKA inhibitor effect). The differences in the participation of PKA versus PKG observed when the inhibitors of PDE3 and PDE4 were used alone or together could be due to differences in the degree of accumulation of cyclic AMP, resulting in the activation of PKA or PKG,

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which are differently localized in the cell and differently associated to PDE3 and PDE4 (Fig. 8). These data argue for a compartmentation of cAMP and cGMP regulated by PDE4 and PDE3 in rat aorta, with the participation of PKA or PKG depending on the cellular pathway used to increase the cAMP level (Eckly-Michel et al., 1997b; Lugnier et al., 1999a). Moreover, in rat aorta without endothelium and in the absence of extracellular calcium, PDE1 and PDE3 seem to play an important role as modulators of rat aortic smooth muscle contractility (Noguera et al., 2001). PDE5, which is mainly present in vascular smooth muscle, participates to vascular contraction since zaprinast increases cGMP level and relaxes rat aorta (Schoeffter et al., 1987), with this effect being endothelium-dependent (Martin et al., 1986; Komas et al., 1991b). The recent discovery of sildenafil, a very potent and selective inhibitor of PDE5, allowed going further in the investigation of PDE5 participation in vascular contraction (Pauvert et al., 2003). Sildenafil inhibits potently vascular smooth muscle PDE5, which is mainly cytosolic, with an IC50 of 3.4 nM, and induces vasorelaxation, with an EC50 of 11 nM; this effect in pulmonary rat artery is not altered by endothelium removal or in the presence of potent inhibitors of PKG and PKA. Moreover, in isolated arterial myocytes, sildenafil (10 –100 nM) antagonized ATP- and endothelin-1-induced calcium oscillations but had no effect on the transient caffeine-induced [Ca2+]I response, indicating that PDE5 may be involved in the inositol triphosphate-mediated calcium signaling pathway (Pauvert et al., 2003). Endothelial cell

NO NO donnors Guanylyl cyclase PDE3 inhibitor

PDE4 inhibitor cGMP PDE3

PDE4

Vmax/Km= 30

Vmax/Km= 0.05

cAMP Smooth muscle

Fig. 7. NO induces the cross-talk between PDE3 and PDE4 in mediating vasodilatation. In smooth muscle cells, basal cAMP levels are regulated by PDE3 since PDE3 has a higher V max/K m ratio than does PDE4. In the absence of endothelium, the addition of either cGMP itself, NO donor (which stimulates guanylyl cyclase), or PDE3 inhibitor induces an increase in cAMP content. This allows the participation of PDE4 in regulating cAMP metabolism. Consequently, PDE4 inhibition by its specific inhibitors results in an increase in cAMP levels and vasodilatation. In the presence of a functional endothelium, the NO produced stimulates soluble guanylyl cyclase, increasing cGMP levels. This latter increase in cGMP inhibits PDE3, allowing PDE4 participation in cAMP regulation. Altogether, in vascular smooth muscle, NO induces a cAMP-related vasodilatation mediated by a cross-talk between PDE3 and PDE4 (Komas et al., 1991a, 1991b; Lugnier & Komas, 1993).

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Low β stimulation or

PDE3 inhibition

PDE3 + PDE4 inhibitions

PDE4 inhibition cAMP

cAMP cAMP

localized PKG activation

localized PKG activation PKA activation

[Ca 2+ ] i vasodilatation

vasodilatation

vasodilatation

Fig. 8. Compartimentalized PDE3/PDE4-mediated vasodilatation. Low h stimulation (0.01 to 0.3 AM isoprenaline) of rat aorta induced vasodilatation mediated by PKA. PDE3 or PDE4 inhibitor induces an increase in cAMP and allows PKG-mediated vasodilatation. PDE4 inhibition, contrary to isoprenaline, induces in isolated vascular myocytes a PKG-mediated decrease of intracellular calcium. Simultaneous inhibitions of PDE3 and PDE4, increasing cAMP at higher level, induce a PKA-mediated vasodilatation. Thus, these findings lend support for both PKA and PKG involvement in cyclic AMP-mediated relaxation in rat aorta. Their involvement depends on the cellular pathway used to increase the cyclic AMP level, since the differences in the degree of accumulation of cyclic AMP result in the activation of PKG or PKA, which are differently localized in the cell (Eckly-Michel et al., 1997a, 1997b).

One cannot exclude that these different modes of PDE participation in vascular and cardiac contractions, including calcium regulation, may also participate in other cellular and tissue function, implicating a cross-talk between the various PDEs as well as a cross-activation of cyclic nucleotides towards protein kinases.

6. 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), which stimulates endothelial cells to migrate, proliferate, and differentiate to form new lumen vessels. Therefore, human umbilical vein endothelial cell (HUVEC) was used as a model of in vitro angiogenesis (Ilan et al., 1998) and the chicken embryo chorioallantoic membrane (CAM) as an in vivo model (Auerbach et al., 1974) to investigate the intracellular signaling mechanisms that are governed by VEGF during angiogenesis. PDE2, PDE3, PDE4, and PDE5 were characterized in HUVEC, the major cAMP-PDE activity being mainly due to PDE2, PDE3, and PDE4 (Favot

Messenger

VEGF + NO

5 ’ AMP

cGMP Stimulation of cell cycle, cell proliferation, and cell migration

PDE2 , PDE4

PDE2

cAMP

5 ’ GMP

PDE2 and PDE4 inhibitors

Increase in cAMP Inhibition of cell cycle, cell proliferation, and cell migration

Fig. 9. PDE regulation in VEGF-stimulated human umbilical endothelial cells (HUVEC). In HUVEC, VEGF induces nitric oxide synthase and, consequently, cGMP-mediated stimulation of cell proliferation and cell migration, which result in angiogenesis. In contrast, an increase in cAMP inhibits cell proliferation and cell migration. Both cAMP and cGMP levels in HUVEC are mainly dependent on PDE2 (which hydrolyses both cAMP and cGMP and is activated by cGMP) and on PDE4 (specific for cAMP and insensitive to cGMP). VEGF induces an increase of PDE2 and PDE4 activities associated to their overexpression. The inhibition of PDE2 or PDE4 in VEGF-stimulated HUVEC induces an increase in cAMP level, associated to an inhibition of cell cycle progression, cell proliferation, and migration. Thus, this suggests that PDE2 and PDE4 participate to angiogenesis and that specific inhibition of PDEs up-regulated during angiogenesis might be new potential target for anti-angiogenic drugs (Favot et al., 2003, 2004).

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et al., 2003). Since PDE2 is activated by cGMP whereas PDE3 is inhibited, the study was focused on PDE2, which can be activated by NO via cGMP, and on PDE4, which is insensitive to cGMP. By using EHNA as a PDE2 inhibitor and RP 7034 as a PDE4 inhibitor, the study shows that in VEGF-stimulated HUVEC, PDE2 or PDE4 inhibitor increases cAMP level as well as VEGF-induced HUVEC migration and proliferation (Fig. 9). Furthermore, PDE4 inhibition blocks the cell cycle progression by reducing cell number in the S phase, whereas PDE2 inhibition decreases the cell proportion in the G2/M phase; these effects are mimicked with the cAMP analogue, 8-Br-cAMP, except that cAMP reduces cell number only in the S phase. To go deeper in this molecular mechanism, the effect of VEGF was studied on PDE expression as well as on the inhibitory effects of PDE inhibitors on cell cycle protein expression (Fig. 10). The study showed that: (1) VEGF induces an increase in cAMP-PDE activity by up-regulating the expression of PDE2 and PDE4 isozymes; (2) VEGF increases cell cycle progression with an increase in p42/ p44 MAP kinase, cyclin A, and cyclin DI expressions and with a decrease in p21waf1/cip1 and p27kip1 expressions; (3) PDE2 as well as PDE4 inhibitor blocks the VEGF-induced increase in p42/p44 MAP kinase expression; (4) only PDE4 inhibitor blocks the VEGF-induced increase in cyclin A and decrease in p27kip1 expressions; (5) PDE2 inhibitor, contrary to PDE4 inhibitor, enhances the VEGF-induced increase in cyclin A and decrease in p27kip1 expressions; (6) the differences between PDE2 and PDE4 effects suggest compartmentalized effects; (7) PDE2 and PDE4 inhibitors, together, block the VEGF-induced increase in cyclin D1 and decrease in p27kip1 expressions; and (8) the inhibition of VEGF-up-regulated PDE2 and PDE4 reverses the VEGF-

induced alteration in cell cycle protein expression, bringing back endothelial cells to a nonproliferating status. Consequently, PDE2 and PDE4 inhibitions are able to inhibit VEGF-induced endothelial cell proliferation by restoring cell cycle key protein expression (Favot et al., 2004). Furthermore, the combination of PDE2 and PDE4 inhibitors inhibits in vivo angiogenesis in the CAM model (Favot et al., 2003). Altogether, these data suggest that PDE2 and PDE4 represent new potential therapeutic targets in angiogenesis.

7. 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 stress, and so forth. Reciprocally, various pathologies acting on intracellular pathways, as well as on transcription, are able to induce selective alterations in PDE regulation. Since 1 splice variant from 1 PDE family is specifically associated to a tissue as well as to a subcellular structure in a specific functional multipleprotein complex, the PDE splice will specifically and locally regulate the functional state of this complex. Therefore, the use of potent and selective inhibitor of the splice(s) altered in pathologic state to reverse its up-regulation may restore the state, with minimal adverse effects. In another way, in PDE4 inhibitor

PDE2 inhibitor PDE2 inhibitor

VEGF

cAMP-PKA

PDE4 inhibitor

G0

M

387

RAF Cyclin D1 cdk4

G1

G2 Cyclin A, B cdc2

Cyclin E cdk2

MAPK

RAF Cyclin D1 cdk4

G1

G2 Cyclin A, B cdc2

MAPK

p27Kip1

Cyclin A cdk2

PDE2 inhibitor

S

Cyclin E cdk2

p27Kip1

Cyclin A cdk2

p21waf1

VEGF

cAMP-PKA

G0

M

p21waf1

PDE4 inhibitor

S PDE2 inhibitor

PDE4 inhibitor

Fig. 10. Role of PDE2 (left panel) and PDE4 (right panel) inhibitors in VEGF-induced cell cycle progression. VEGF, by stimulating RAF – MAPK cascade, activates cyclin D1 that, in turn, induces cell cycle progression. PKA inactivates Raf-1 and consequently inhibits MAPK cascade. PDE2 inhibitor, as well as PDE4 inhibitor, may counteract the effect of VEGF by activating PKA. PDE2 and PDE4 inhibitors inhibit ERK phosphorylation, decrease cyclin D1 expression, and increase the expression of the cyclin kinase inhibitor p21waf1/cip1. This could be either a direct effect on cyclin D1 level or the result of Raf-1mediated MAPK cascade inactivation. Cyclin A allows cells to go through the S phase and facilitates transition from the S to the G2 phase. Its expression is inhibited by PDE4 inhibitor, whereas it is stimulated by PDE2 inhibitor. The inhibitory effect of PDE2 inhibitor on the expression of P27kip1, inhibitor of cyclin kinase cdk2 and cdk4, may favor cell cycle progression from Go/G1 to S. PDE2 inhibition merely decreases the S – G2/M transition, whereas PDE4 inhibition decreases the Go/G1 – S phase transition. The differences between PDE2 and PDE4 effects may suggest compartmentalized effects of PDE2 and PDE4. Altogether, PDE2 and PDE4 inhibitors are able to inhibit VEGF-induced cell proliferation by restoring cell cycle key protein expression (Favot et al., 2004).

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some pathologies where the splice is down-regulated, gene therapy or the induction of positive regulation at N-terminal domain of the down-regulated splice will be helpful. Many new methodological approaches (Lugnier, 2005) and pharmacological tools, including highly specific PDE inhibitors and PDE antibodies, allow to increase our knowledge concerning PDE implication in many research fields, especially for the newly discovered PDEs. Many PDE splice variant mRNAs were identified in many tissues; however, these characterizations do not preclude for their functional role if the corresponding protein is not present or not active. For this reason, more specific antibodies for the different PDE families, as well as potent and specific inhibitors of PDE subtype and ideally of splice variants, would be very helpful to determine their functional role. Besides the exponential increase of knowledge in PDE field, it is now time to reconsider in a molecular approach previous studies, done mainly by considering cAMP or cGMP global effects, to go deeper in the localized regulation mediated by specific PDE subtypes in normal as well as in pathological states. There is no doubt that this will bring a revival in therapeutic approaches.

Acknowledgment Dr The´re`se Keravis (CNRSUMR 7034, Strasbourg) is greatly acknowledged for her critical reading of the manuscript.

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