Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.
Introduction
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The Phosphodiesterase (PDE) Superfamily
General structure
cAMP and cGMP signaling pathways
Compartmentalization of cyclic nucleotide signaling pathways
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PDE Families
PDE1
PDE2
PDE3
PDE4
PDE5
PDE6
PDE7
PDE8
PDE9
PDE10
PDE11
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PDE Inhibitors
Overview
PDE5 inhibitors and their clinical use in erectile dysfunction, pulmonary hypertension, and other disorders
PDE4 inhibitors and their promising clinical uses
PDE inhibitors and the cardiovascular system
PDE inhibitors and cancer
Conclusions and Perspectives
I. Introduction
cAMP and cGMP are intracellular second messengers that play a central role in signal transduction cascades that regulate many critical physiological and pathophysiological processes, including cellular growth, differentiation, and proliferation; Ca2+-dependent signaling; reproduction; cardiac function; vision; inflammation; and tumor development. As seen in Figure 1, adenylyl and guanylyl cyclases catalyze formation of cAMP and cGMP from ATP and GTP, respectively. Signal transduction is initiated by cAMP- and cGMP-induced activation of cAMP- and cGMP-dependent protein kinases (PKA and PKG, respectively), with subsequent phosphorylation of key proteins and activation of downstream pathways. In addition, cyclic nucleotide binding proteins serve as direct signal transducers, ie, cAMP-activated guanine nucleotide exchange proteins (EPACs) that regulate Rap GTPases (guanine nucleotide triphosphatases), cAMP- and cGMP-gated ion channels, and several cyclic nucleotide phosphodiesterases (PDEs), especially PDE2, -5, and -6, which contain allosteric, noncatalytic, cyclic nucleotide-binding domains (Figure 1).
Figure 1.
Cyclic nucleotide signaling and regulation. AC, adenylyl cyclase; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; B-Raf, B-Raf protein kinase; CNG-channel, cyclic nucleotide-gated channel; CNP, C-type natriuretic peptide; pGC, particulate guanylyl cyclase; PKG, cGMP-dependent protein kinase; Rap, Ras-related protein; sAC soluble AC; sGC, soluble guanylyl cyclase.
II. The Phosphodiesterase (PDE) Superfamily
PDEs, which were identified almost immediately after the discovery of cAMP (1–3), represent a large family of ubiquitously expressed hydrolases that control the intracellular levels of cyclic nucleotides by hydrolyzing cAMP and cGMP to 5′AMP and 5′GMP, respectively. Because they catalyze the sole known enzymatic reaction for terminating cyclic nucleotide signals, PDEs are critical regulators of the myriad physiological and pathophysiological processes under cyclic nucleotide control in health and disease.
PDEs constitute a large and complex superfamily that contains 11 PDE gene families (PDE1 to PDE11), comprising 21 genes that generate approximately 100 (or more) proteins via alternative splicing of mRNA or multiple promoters and transcription start sites (Figures 2 and 3) (4, 5). PDE families are structurally related and highly regulated but differ in primary structures, catalytic properties, responses to specific inhibitors and modulators, and in their subcellular localization and targeting to specific, multimolecular regulatory complexes or “signalosomes.” The 11 PDE families can be grouped into three categories based on their substrate specificity. PDE4, PDE7, and PDE8 selectively hydrolyze cAMP, whereas PDE5, PDE6, and PDE9 hydrolyze cGMP. PDE1, PDE2, PDE3, PDE10, and PDE11 possess dual specificity, acting on both cAMP and cGMP with varying affinities, depending on the isoform (Figure 1) (6). Although there may be some functional redundancy among isoenzymes, most PDE isoforms and variants play specific physiological roles in mammalian cells.
Figure 2.
General structure of PDE enzyme molecules. HD, hydrophobic domains.
Figure 3.
Schematic representation of the structure of each of the 11 human PDE families. HD, hydrophobic domains.
A. General structure
As seen in Figure 2, the different PDEs share common structural determinants (6, 7): 1) a conserved catalytic domain; 2) a regulatory domain between the amino terminus and the catalytic domain; and 3) a region between the catalytic core and the carboxyl terminus that can be phosphorylated by MAPK (PDE4) (8) or prenylated (PDE6) (9).
The catalytic core contains helices that are organized into three subdomains. The active site is formed at the junction of the helices by residues that are highly conserved among all PDEs (10). The substrate binding pocket contains two consensus metal binding domains: one Zn2+ binding motif, and a second binding site whose metal ligand has not been definitively identified. Although Mg2+ is generally considered as the second metal, Mn2+ and Co2+ also support PDE catalytic activity (10). The N-terminal portion of PDE molecules essentially defines specific properties of each member and variant of the PDE gene family (Figures 2 and 3). This region contains targeting domains that are responsible for localization of PDE isoforms to specific subcellular sites, organelles, and membranes, and specific signalosomes. N-Terminal regulatory regions also contain structural determinants that permit different PDEs to respond to specific regulatory signals, including binding sites for effectors and allosteric modulators, sites for covalent modifications, autoinhibitory domains, dimerization domains, motifs and/or domains for specific protein/protein interactions, etc. PDE2, PDE5, PDE6, PDE10, and PDE11 have a protein domain termed cGMP-specific PDEs, adenylyl cyclases and FhIA (GAF), known to be involved in cGMP-mediated allosteric regulation and dimerization of GAF-containing PDEs. PDE1 contains a Ca2+/calmodulin (CaM)-binding site; PDE3, a transmembrane domain; PDE4, upstream conserved regions (UCRs); and PDE8, cheY-homologous receiver domain (REC) domain and a per-arnt-sim (PAS) domain. PDE7 and PDE9 have no other recognized specific protein domains in addition to the PDE catalytic domain (11).
As expected from their complex genomic organization, multiple PDE isoforms are expressed in almost every cell (4–6). Some cells are relatively enriched in specific PDEs, eg, photoreceptor PDE6, which is virtually exclusively expressed in retina rods and cones and in the pineal gland. Figure 4 presents microarray data regarding expression of PDE genes in different human tissues. Recent studies have shown that many PDEs that are tightly connected to different cellular functions are also involved in various pathological conditions (7). For instance, PDE4B abnormalities have been linked to schizophrenia (12), whereas defects in PDE6 subunits cause hereditary eye diseases (13, 14). Recently, genetic alterations in PDE genes were described to be associated with tumor development. Polymorphisms in the genes encoding PDE8A and PDE11A have been associated with a predisposition to developing certain adrenocortical tumors (15) and testicular (16) and prostatic cancer (17).
Figure 4.
PDE tissue expression. Each PDE is considered individually based on its maximum and minimum expression (478–483). Reference: Microarray combined data acquired from the ArrayExpress database (www.ebi.ac.uk/arrayexpress) under the accession numbers E-GEOD-30352, E-AFMX-5, A-AFFY-44, and E-MTAB-513.
Because of their critical roles in intracellular signaling and the possibility for their precise subcellular targeting, PDEs are considered to be very attractive pharmacological targets (4–7). Since the discovery of caffeine as a nonselective, albeit weak, inhibitor of PDE activity, a number of selective and nonselective PDE inhibitors has been identified. Some of them, the most illustrative examples being the selective PDE5 inhibitors sildenafil, vardenafil, and tadalafil, have been successfully used as therapeutic agents for treatment of specific clinical conditions, ie, erectile dysfunction and pulmonary hypertension (4–7). This review describes the known properties, mechanisms for regulation, expression patterns, and physiological and pathophysiological functions of the different PDE enzymes. We also discuss the therapeutic potential of certain PDE inhibitors.
B. cAMP and cGMP signaling pathways
Signaling via cyclic nucleotide pathways is central to the function of numerous biological systems. cAMP is typically produced by hormonal stimulation of seven-transmembrane G protein-coupled receptors (GPCRs) (18–20). Ligand binding to the appropriate GPCR activates the Gs α-subunit of the G protein complex, which exchanges GDP for GTP and is subsequently released from the complex. The activated Gs α-subunit stimulates membrane-associated adenylyl cyclases to convert ATP into cAMP, which in turn activates protein kinase A (PKA), EPAC, or cyclic nucleotide-gated channels (CNGCs) (21–23). This signaling is terminated when cAMP is degraded by one of the PDE enzymes (Figure 1) (24, 25).
PKA is a heterotetramer that consists of two regulatory and two catalytic subunits and exists in two forms: type I PKA and type II PKA holoenzymes (23, 26). The subcellular localization and compartmentalization of PKA is controlled through association with A-kinase-anchoring proteins (AKAPs) (27). When intracellular cAMP increases, cAMP binds to the regulatory subunits (PKA RI and RII) of PKA and causes dissociation of active catalytic subunits. Unbound PKA catalytic subunits then phosphorylate various target proteins (23). One of them is the transcription factor cAMP response element-binding protein (CREB), which is involved in the regulation of expression of many genes related to cell metabolism and proliferation (23, 26).
EPAC and CNGC are other targets that are also known to be involved in mediating cAMP responses. cAMP directly binds to and activates EPAC, which in turn activates Rap protein through guanine-nucleotide exchange of the small GTPases Rap1 and Rap2 (22). Downstream of Rap, a variety of effectors have been implicated in the control of a variety of processes, including integrin-mediated cell adhesion and cell-cell junction formation (22), exocytosis (28–30), insulin secretion (31), and cardiomyocyte function (32). Cyclic nucleotides also bind to and directly activate CNGC (33). CNGCs are voltage-dependent cation channels, which are found in many tissues, including heart, kidney, brain, and sperm. In photoreceptors and olfactory sensory neurons, CNGCs convert sensory stimuli into electrical and biochemical responses and play critical roles in visual transduction and olfaction, respectively. Photoreceptor CNGCs are more sensitive to cGMP than cAMP, whereas olfactory receptor CNGCs are sensitive to both cGMP and cAMP (21, 33). Mutations in photoreceptor CNGCs are associated with retinal degeneration and color blindness (34).
cGMP is generated via stimulation of cytosolic guanylyl cyclase by nitric oxide (NO), or of membranous guanylyl cyclase by the natriuretic peptides. Particular guanylyl cyclases contain, in a single molecule, both the cyclase catalytic domain and natriuretic peptide receptors and are stimulated by structurally related polypeptide hormones that include atrial natriuretic peptide, type-B natriuretic peptide, and type-C natriuretic peptide, derived from the atria and ventricles of the heart and from endothelial cells, respectively (35–37).
NO, a gaseous signaling molecule that is endogenously synthesized from L-arginine by the catalytic action of NO synthases (NOSs), activates soluble guanylyl cyclase to produce cGMP. Three NOS isoenzymes have been described, including neuronal and endothelial NOS, both constitutively expressed and Ca2+/CaM-activated, and inducible NOS, which is induced by inflammatory stimuli and is Ca2+-independent. Many tissues, including cardiac myocytes, express all three isoforms (38–42).
cGMP exerts its physiological action through cGMP-dependent protein kinase (PKG), cGMP-regulated PDEs, and cGMP-gated ion channels. Two PKG isoforms, encoded by different genes, have been identified: PKGI, the primary isoform in the cardiovascular system, and PKGII. PKG catalyzes the phosphorylation of a number of physiologically relevant proteins involved in regulation of cardiovascular function (43), including cardiac contractility and vascular tone (44). cGMP regulates neurotransmission and exerts anti-inflammatory and antiapoptotic effects. cGMP also inhibits platelet aggregation and oocyte maturation (cf Section II.C), in part by inhibiting PDE3 and thereby increasing cAMP (45, 46). On the other hand (cf Section II.C), in specialized compartments of mouse heart, NO-induced increases in cGMP activate PDE2 (the “so-called” cGMP-stimulated cAMP PDE), leading to increased hydrolysis of cAMP and, consequently, inhibition of the effects of β1-receptor- and β2-receptor-mediated activation of cAMP/PKA signaling and cardiac function (47).
C. Compartmentalization of cyclic nucleotide signaling pathways
Intracellular concentrations of cyclic nucleotides are tightly regulated, and their downstream signaling pathways are temporally, spatially, and functionally compartmentalized. In rodent cardiomyocytes, for example, early studies demonstrated that although both epinephrine and PGE1 increased cAMP and activated PKA, they regulated distinct pools of cAMP, with only epinephrine increasing the strength of myocardial contraction and activating phosphorylase (48). More recent studies using genetically encoded fluorescence resonance energy transfer (FRET)-imaging sensors (EPAC- or PKA-based or PKA substrate-based cAMP sensors) and other biosensors such as cyclic nucleotide-sensitive ion channels have verified this compartmentalization of cyclic nucleotides and their signaling pathways (49–51). For example, by targeting PKA-RI/EPAC and PKA-RII/EPAC FRET cAMP sensors to various AKAPs, tethered at different subcellular locations, real-time imaging of cAMP signals in cardiomyocytes demonstrated that catecholamines and PGE1 did indeed generate spatially distinct, compartmentalized pools of cAMP, which did activate distinct PKA/cAMP signaling pathways and elicit different functional outputs (52). In other experiments with rat ventricular myocytes, cAMP concentrations in the subsarcolemmal and cytosolic compartments were measured in the basal state and after stimulation of the β-adrenergic receptor (β-AR), using recombinant CNGCs and FRET-based RI-EPAC and RII-EPAC sensors (53). Live-cell imaging of changes in cAMP, generated via inhibition of PDE3 and/or PDE4, were consistent with the presence of distinct functional subcellular compartments and different spatiotemporal contributions of PDE3 and PDE4 isoforms to the β-AR response in cardiac myocytes, with PDE3 regulating a cAMP pool important for basal myocardial contractility and PDE4 regulating the β-AR-responsive compartment (53). Thus, despite activation of cAMP and cGMP signals by diverse stimuli, this compartmentation and spatial control of cAMP signal transducers and effectors allows for regulation of individual, specific signaling pathways for propagation of signals along these defined pathways, and for maintenance of the specificity of downstream signals and biological responses.
The molecular basis for compartmentalization of cyclic nucleotide-signaling pathways involves the specific subcellular targeting/tethering (either stable or dynamic) of distinct and unique combinations of scaffolding molecules (including AKAPs, β-arrestin, caveolin, etc), cyclic nucleotide effectors (cyclases, PKAs, PKGs, EPACs, protein phosphatases [PPs]), and many types of regulatory effectors, including ERKs (50, 51, 54–56). Specific PDEs or subsets of PDEs are major contributors to this compartmentalization via their recruitment and integration, in an isoform-specific manner, into these unique multimolecular regulatory signaling complexes, defined as “signalosomes” (54). Thus, as components of specific signalosomes, PDEs affect spatiotemporal regulation of distinct cAMP signaling pathways, and control cyclic nucleotide concentrations and gradients critical to transduction of specific cyclic nucleotide signals and generation/modulation of specific physiological and pathophysiological responses. PDEs regulate specificity of signaling in two ways: by tight temporal and spatial regulation of cyclic nucleotide gradients within specific compartments, and by preventing diffusion of signals into neighboring compartments. Compartmentalization of specific PDE-containing signalosomes demonstrates that subcellular localization of PDEs, not their concentrations, determines specific roles for individual PDEs in regulating specific cAMP-signaling pathways (50, 51, 54–56).
One group of scaffolding molecules, the very large AKAP family, plays a central role in compartmentalization of cAMP- signaling pathways (54–56). As depicted in Figures 5 and 6, AKAPs serve multiple functions, ie, as tethers for PKA at many different subcellular locations near PKA substrates for their selective phosphorylation, and as scaffolds for signalosomes with different proportions of PKA, adenylyl cyclases, other kinases, phosphatases, EPACs, PDEs, PKA substrates, and other effector molecules, including ERK. As indicated in Table 1 and depicted in Figures 5 and 6, the widespread intercellular distribution of different AKAPs allows for the assembly of many cAMP-centered signalosomes, with different PDE isoforms, that regulate specific cAMP-signaling pathways in specific functional compartments (54–56). The presence of phosphatases and PDEs, especially PDE3 and PDE4, allows these cAMP-centered signalosomes to be self-modulatory (Figure 5). The AKAP-based signalosomes effectively compartmentalize PKA-induced phosphorylation of substrates and regulation of downstream responses. In these signalosomes, cAMP-induced activation of PKA also results in phosphorylation of PDE3 or PDE4, resulting in termination of the cAMP signal. In addition, protein phosphatase-induced dephosphorylation of phosphoPDEs and phosphoPKA substrates also allows the cAMP signalosome complex to return to its basal state. Thus, PKA-AKAP-PDE complexes tightly regulate and focus cAMP action to very specific cellular microdomains and microenvironments (57).
Figure 5.
AKAPs: scaffolds for PDE-containing signalosomes.
Figure 6.
Myocardial AKAPs. The subcellular localization of different AKAPs is shown, together with their effector proteins. Cav1.2 is regulated by cAMP confined to specific signaling domains. β1- and β2-ARs are associated with Cav1.2 and AKAPs (AKAP79 and AKAP15/18α), which regulate cAMP production and channel activity. AKAP79/150 has a CaN binding domain and is one of the endogenous inhibitors of CaN. Yotiao and KCNQ1 regulate potassium ion current. PDE3A/AKAP18δ/PLB/SERCA2 regulate Ca2+ reuptake. PI3K p110γ/PDE3B complex regulates cAMP and myocardial function. Troponin T, synemin, and myospryn are sarcomeric AKAPs. Synemin is localized at the Z-disk and binds to actinin and desmin to act as a mechanical linker. D-AKAP1 and -2 are localized at the mitochondrial membrane. Expression of AKAP-LBC is critical in the hypertrophic response. mAKAP is specifically localized at, and anchors PKA to, the SR and nuclear membranes. mAKAP interacts with RYR2 and PDE4. AKAP95 is localized at the nuclear membrane, exhibits a cell cycle-dependent interaction with PKA, and coordinates a scaffold of hormonally responsive transcription complexes. A complex of MTG-PKA and PDE7A is shown at Golgi. CaV1.2, LTCCs; KCNQ, IKS potassium channel subunit; SKIP, sphingosine kinase-interacting protein; MTG, myeloid translocation gene; CaN, calcineurin.
Table 1.
AKAPs: Scaffolds for PDE-Containing Signalosomes
PDEs | AKAPs | Effectors | Ref. |
---|---|---|---|
PDE3A | AKAP18δ | PKA-RII, Serca2, PP2A, PLB | 395 |
PDE3B | P110γ | PKA, phosphoinositide, β-AR | 396 |
PDE4A | AKAP149, AKAP95, MTG | PKA-RII | 397 |
PDE4A | AKAP3 (110) | PKA | 398 |
PDE4C | AKAP9 (450, Yotiao) | PKA-RII | 399 |
PDE4D | AKAP5 (75/79) | PKA, β-AR, phospho-Erk | 400 |
Myomegalin (PDE4DIP) | PKA, cardiac troponin I (cTNI), β-AR | 401 | |
PDE4D3 | mAKAP | PKA, EPAC1, Erk5 | 32 |
AKAP9 (450, Yotiao) | IKS (slowly activating potassium current), KCNQ1, KCNE1, PKA, PP1 | 402 | |
AKAP9 (450, Yotiao) | PKA-RII | 399, 403 | |
PDE4D5 | AKAP5 (75/79) | PKA, β-arrestin, β2-AR, Erk | 154 |
PDE4D8 | AKAP5 (75/79) | PKA | 404 |
PDE7A | MTG | PKA | 397 |
Abbreviation: myeloid translocation gene.
Several PDE isoforms have been found to play critical roles in modulating multiple signaling pathways by regulating compartmentalized cAMP signaling through interaction with different AKAPs and their effectors. AKAPs play a role in anchoring PKA in close proximity to their specific substrates and as scaffold molecules for coordinated assembly of multimolecular signaling complexes called “signalosomes” that contain PDEs and thereby regulate cAMP signaling pathways.
As seen in Figure 7A, recent studies suggest that in mouse heart, PDE3A, as a key component of an AKAP 18δ-based signalosome (Table 1), regulates basal myocardial contractility by controlling cAMP/PKA-mediated activation of the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2) and Ca2+ uptake into the SR during the relaxation phase (diastole) of the myocardial contractile cycle (58). This SERCA2 regulatory signalosome includes AKAP 18δ, SERCA2, phospholamban (PLB), PDE3A, PKA C, PKA-RII, and PP2A. As depicted in Figure 7B, PKA phosphorylates PLB, leading to its dissociation from, and activation of, SERCA2 and Ca2+ uptake into the SR. PKA also phosphorylates and activates PDE3A, leading to hydrolysis of cAMP and termination of the cAMP signal. PP2A dephosphorylates PDE3A and PLB, allowing return of the AKAP/SERCA2 regulatory signalosome to its basal state (59).
Figure 7.
PDE3A regulates SERCA2-mediated Ca2+ uptake into the SR. A, The diagram illustrates some of the physiological interactions and interplay between two intracellular second messengers, cAMP and calcium, in regulation of the excitation contractile cycle in cardiac myocytes (blue for cAMP; green for calcium) (58, 59). PDE3A regulates SERCA2-mediated Ca2+ uptake into the SR by modulating cAMP/PKA-induced phosphorylation of PLB (pPLB) (395). PLB, an endogenous muscle-specific SERCA2 inhibitor, interacts with SERCA2 and PDE3A and determines the rate of calcium reuptake into the SR, after its release from myofilaments at the end of the contractile phase of the cycle. PKA-mediated phosphorylation of PLB dissociates PLB from SERCA2, allowing for faster calcium reuptake into the SR. PDE3A mediates cAMP/PKA signaling as a component of a signalosome containing AKAP18δ/SERCA2/PKA/PP2A. B, The SERCA2 regulatory signalosome (395). In the basal state, PLB remains bound to SERCA2 and inhibits calcium uptake. Activation of PKA by cAMP results in the phosphorylation of PLB and PDE3A. Phosphorylated PLB (pPLB) dissociates from SERCA2, increasing its calcium ATPase activity, but the integration of phosphorylated PDE3A into the complex limits this effect by increasing hydrolysis of cAMP. PP1 and PP2A in the complex would be expected to catalyze the dephosphorylation of PDE3A, PLB, and other PKA substrates, and return the SERCA2 complex to its basal state. PMCA, plasma-membrane Ca2+-ATPases; NCX, Na+/Ca2+ exchangers.
As also seen in Table 1 and Figure 6, different PDE4 isoforms are components of many AKAP-based signalosomes at many different subcellular locations. For example, AKAP15/18 and muscle-specific AKAP (mAKAP) target PKA and PDE4B and PDE4D to L-type Ca2+ channels (LTCCs) and ryanodine receptor (RyR) 2 channels, respectively, where they regulate cAMP/PKA-stimulated Ca2+ influx into the cardiomyocyte and Ca2+-induced Ca2+ release from the SR (60–62), respectively. Thus, as components of three distinct AKAP-based signalosomes targeted to LTCCs and RyR2 channels and the SERCA2 pump, respectively, PDE4B, PDE4D, and PDE3A regulate cAMP/PKA-induced activation of the excitation/contraction cycle (58–62). In addition to AKAP-based signalosomes, the large number of PDE4 isoforms are components of signalosomes that utilize many different scaffold proteins and effectors, including phosphatidylinositol-3 kinase (PI3K)-γ, EPAC1, receptor for activated c-kinase-1, β-arrestin, DISC1 (Dishelved in schizophrenia), lissencephaly-1, etc (50, 63).
In addition to modulating activities of LTCCs and RyR2 channels, PDE4 isoforms also regulate β-AR signaling in the heart via their interaction with β-ARs themselves (64, 65) and via cross talk with the cGMP-signaling system (47). Catecholamine-induced activation of β1-AR and β2-AR activates distinct cAMP-signaling pathways to produce different biological effects, with β1-AR signaling producing a much greater increase in heart rate and contractility than β2-AR signaling. Chronic β1-AR signaling leads to apoptosis, whereas chronic β2-AR signaling promotes survival (64, 65). As seen in Figure 8, the unoccupied β1-AR directly associates with PDE4D8, maintaining low cAMP levels and reduced cAMP/PKA signaling near the receptor. As also depicted in Figure 8, when the β1-AR is occupied or activated by either an agonist or antagonist, PDE4D5 dissociates from the receptor (64, 65). On the other hand, the unoccupied β2-AR does not bind PDE4D isoforms, but the occupied/activated β2-AR complex recruits/associates with a preformed β-arrestin/PDE4D5 complex (64). It is thought that these divergent interactions of PDE4D isoforms with β1-AR and β2-AR (Figure 8) contribute to the temporal and spatial differences in local cAMP signaling near the β1- and β2-ARs and also contribute to the characteristics and specificity of the downstream signals and effects generated by activated β1- and β2-ARs (64, 65).
Figure 8.
Spatially defined regulation of myocardial β1- and β2-AR/cAMP signaling. cAMP and cGMP are intracellular second messengers involved in the regulation of myocardial contractility and are under tight control by cyclic nucleotide degrading enzymes PDEs. A, In caveolae of myocytes, β1- and β2-adrenergic signaling mediates the positive inotropic effects of catecholamine via cAMP generation and PKA activation. Under basal conditions, a complex of PDE4D8 and the β1-AR is likely responsible for regulation of local cAMP concentrations and PKA activity, and PDE4D8 dissociates from the complex after ligand binding and activation of β1-AR. PDE4D5 is not associated with β2-AR, but after ligand binding, a preformed complex of β-arrestin and PDE4D5 is recruited to the β2-AR-signaling complex (64, 65). B, cAMP generated via activation of β1/β2 receptors can be counteracted by β3-AR signaling which generates NO, leading to sGC activation, synthesis of cGMP, and activation of PDE2. cGMP allosterically activates PDE2 via its binding to regulatory PDE2 GAF-B domains and increases cAMP hydrolysis. This action defines a key role for compartmentalized PDE2 in the β3-AR-activated feedback loop. cGMP generated by β3-AR/NO/cGMP pathway can reduce cAMP signals and β-adrenergic-induced cardiac inotropy via increased cAMP hydrolysis caused by cGMP-activated PDE2. GPCRs other than β-AR are localized outside of such a signaling loop and activate a separate pool of AC. AC, adenylate cyclase; eNOS, endothelial NOS; P, phosphorylation; sGC, soluble guanylyl cyclase.
Although PDE2 accounts for approximately 3% of total PDE activity in neonatal rat cardiomyocytes, its activation by cGMP and its localization in a spatially defined membrane compartment allows it to integrate cAMP and cGMP signals and control NO-induced down-regulation of much of the cAMP generated by β1- or β2-adrenergic agonists (47). As depicted in Figure 8, β3-AR signaling generates NO, which activates soluble guanylate cyclase (sGC) to produce cGMP, leading to allosteric activation of PDE2, via its binding to regulatory PDE2 GAF-B domains and to increased hydrolysis of cAMP. This action defines a key role for compartmentalized PDE2 in the β3-AR activated feedback loop. cGMP, generated by the β3-AR/NO/cGMP pathway, allosterically activates PDE2 and thereby reduces cAMP signals and β-AR-induced cardiac inotropy (47).
Some compartmentalization of cyclic nucleotide signaling pathways occurs at the cellular level. As seen in Figure 9, the control of meiotic progression and female fertility by PDE3A (45) reflects both generation of distinct cGMP and cAMP signals in two different cells, ie, ovarian cumulus granulosa cells and oocytes, respectively, as well as the integration of signaling pathways and coordination of communication networks between the two cells (66–68). Although competent to complete meiosis, mammalian oocytes are physiologically arrested in prophase I (prophase of the first meiotic division) until shortly before ovulation. As seen in Figure 9, in murine oocytes, cAMP, most likely via PKA-catalyzed phosphorylation of downstream effectors, including Cdc25B and Wee 1 kinase, inhibits activation of maturation-promoting factor (MPF), and thereby inhibits oocyte maturation and maintains meiotic arrest (45, 69). Elevated intra-oocyte cAMP concentrations are most likely maintained by constitutively active oocyte G protein-linked receptors, which activate oocyte adenylyl cyclase, and by cGMP-mediated inhibition of oocyte PDE3A, which results from diffusion of cGMP into oocytes from surrounding cumulus cells through gap junctions (66–69). PDE3A, relatively highly expressed in mammalian oocytes, is the predominant PDE responsible for hydrolysis of oocyte cAMP (45, 70). Current thinking suggests that resumption of meiosis is triggered by LH, which increases cAMP and reduces cGMP in cumulus cells, leading to closure of gap junctions and a decrease in oocyte cGMP (66–69). This relieves cGMP-induced inhibition of oocyte PDE3A, resulting in PDE3A-induced hydrolysis of oocyte cAMP (69, 70), and resumption of meiotic maturation. PDE3A female knockout mice are sterile, most likely due to the absence of PDE3A in oocytes, which leads to increased oocyte cAMP content, activation of PKA, inhibition of MPF, and subsequent PKA-induced meiotic block at the G2/M transition (45).
Figure 9.
Effects of PDE3A on regulation of cAMP/PKA signaling during meiotic progression in mice oocytes (45, 66–69). PDE3A is relatively highly expressed in mammalian oocytes and is the predominant PDE responsible for hydrolysis of oocyte cAMP. In preovulatory murine oocytes, increased intra-oocyte cAMP concentrations are most likely maintained by constitutively active oocyte G protein-linked receptors that activate oocyte adenylyl cyclase and by cGMP-mediated inhibition of oocyte PDE3A, which results from diffusion of cGMP into oocytes from surrounding cumulus cells through gap junctions. Elevated cAMP and activated PKA phosphorylate and inhibit Cdc25B and phosphorylate/activate Wee1 kinase, which in turn catalyzes inhibitory phosphorylation of MPF (Cdc2/cyclin B complex). The integrated effect of these PKA-induced phosphorylations is inactivation of MPF and maintenance of G2/M meiotic arrest. Resumption of meiosis is triggered by LH, which increases cAMP and reduces cGMP in cumulus cells, leading to closure of gap junctions and a decrease in oocyte cGMP. This relieves cGMP-induced inhibition of oocyte PDE3A, resulting in PDE3A-induced hydrolysis of oocyte cAMP, reduction in PKA activation, activation of MPF, and resumption of meiotic maturation.
Attempts to understand the molecular underpinnings of these compartments has not only identified specific functional roles of many individual PDEs in compartmentalized regulation of specific cyclic nucleotide signaling pathways and physiological and pathophysiological responses but also has identified many new targets for novel therapeutics, as well as the need to design novel targeting strategies.
III. PDE Families
An overview of the classification, expression, and regulation/function of all PDE enzymes (as well as the general characteristics of the PDE genes) is shown in Tables 2 and 3, respectively. In the following paragraphs, we discuss the characteristic features of each PDE family individually.
Table 2.
Gene Family | Regulation | Substrate Specificity | Intracellular Localization | Main Functions | Ref. |
---|---|---|---|---|---|
PDE1 | Ca2+/CaM-activated | cAMP, cGMP | Cytosolic | Vascular smooth muscle contraction, sperm function (PDE1A) | 72, 82, 83, 406–408 |
Dopaminergic signaling, immune cell activation, and survival (PDE1B) | |||||
Vascular smooth muscle cell proliferation, sperm function, neuronal signaling (PDE1C) | |||||
PDE2 | cGMP-activated | cAMP, cGMP | Membrane-bound or cytosolic | Regulates aldosterone secretion, phosphorylation of calcium channels in heart, cGMP in neurons; endothelial cell function under inflammatory conditions | 47, 101, 406, 409 |
PDE3 | cGMP-inhibited | cAMP, cGMP | Membrane-bound or cytosolic | Cardiac contractility, platelet aggregation, vascular smooth muscle contraction, oocyte maturation, renin release (PDE3A) | 119, 395, 410–413 |
Insulin signaling, cell cycle/proliferation (PDE3B) | |||||
PDE4 | cGMP-insensitive | cAMP | Membrane-bound or cytosolic | Brain function, monocyte and macrophage activation, neutrophil infiltration, vascular smooth muscle proliferation, fertility, vasodilatation, cardiac contractility | 395, 414–419 |
PDE5 | PKA-PKG-phosphorylated | cGMP | Cytosolic | Vascular smooth muscle contraction, platelet aggregation, cGMP signaling in brain | 406, 419–421 |
PDE6 | cGMP-activated | cGMP | Cytosolic | Phototransduction | 208, 422 |
PDE7 | Rolipram-insensitive | cAMP | Cytosolic | Immune cell activation (PDE7A) | 223, 423, 424 |
Memory function and excreteT (PDE7B) | |||||
PDE8 | cAMP-specific | cAMP | Membrane-bound or cytosolic | T-cell activation, sperm or Leydig cell function, T4 and T3 production (PDE8A) | 239, 243, 250 |
PDE9 | cGMP-specific | cGMP | Cytosolic or nuclear | NO-cGMP signaling in brain | 260, 425 |
PDE10 | Unknown | cAMP, cGMP | Cytosolic or particulate | Learning and memory | 279, 281, 406 |
PDE11 | Unknown | cAMP, cGMP | Cytosolic | Sperm development and function | 16, 17, 426, 427 |
According to the most widely used consensus system, created in 1994 (428), the PDEs are named as follows: first, the abbreviation PDE, which denotes a 3′,5′ cyclic nucleotide PDE; second, an Arabic numeral referring to the gene family; third, a capital letter indicating the individual gene product according to the order of appearance in GenBank (ie, “A” usually, but not always, refers to the first member of the family reported; “B” refers to the second gene to be reported, etc); and finally, an Arabic number denoting the spliced variant. For instance, PDE10A1 stands for a PDE from family 10, the first identified gene, A, isoform 1.
Table 3.
PDE Genes
Gene | No. of Transcripts | Isoforms (Protein Coding) | Size Range, aa | Chromosome Locationa |
---|---|---|---|---|
PDE1A | 13 | 4 | 535–545 | 2q32.1 chr2:183,004,763-183,387,919 |
PDE1B | 8 | 2 | 516–536 | 12q13.2 chr12:54,943,134-54,973,023 |
PDE1C | 11 | 5 | 634–769 | 17p14.3 chr7:31,790,793-32,338,941 |
PDE2A | 27 | 4 | 932–941 | 11q13.4 chr11:72,287,185-72,385,635 |
PDE3A | 3 | 1 | 1141 | 12p12.2 chr12:20,522,179-20,837,315 |
PDE3B | 5 | 1 | 1112 | 11p15.2 chr11:14,665,269-14,892,350 |
PDE4A | 10 | 4 | 647–886 | 19p13.2 chr19:10,527,449-10,580,305 |
PDE4B | 19 | 5 | 564–736 | 1p31.3 chr1:66,258,197-66,840,259 |
PDE4C | 16 | 5 | 606–712 | 19p13.11 chr19:18,318,771-18,366,229 |
PDE4D | 27 | 9 | 507–809 | 5q11.2-q12.1 chr5:58,264,865-59,817,947 |
PDE5A | 12 | 2 | 833–875 | 4q26 chr4:120,415,550-120,550,146 |
PDE6A | 3 | 1 | 860 | 5q32 chr5:149,237,519-149,324,356 |
PDE6B | 12 | 3 | 575–854 | 4p16.3 chr4:619,373-664,571 |
PDE6C | 2 | 1 | 858 | 10q23.33 chr10:95,372,345-95,425,767 |
PDE7A | 8 | 2 | 456–482 | 8q13.1 chr8:66,629,745-66,754,557 |
PDE7B | 2 | 1 | 450 | 6q23.3 chr6:136,172,834-136,516,712 |
PDE8A | 16 | 3 | 783–829 | 15q25.3 chr15:85,523,671-85,682,376 |
PDE8B | 9 | 5 | 788–885 | 5q13.3 chr5:76,506,274-76,725,632 |
PDE9A | 29 | 13 | 433–593 | 21q22.3 chr21:44,073,746-44,195,619 |
PDE10A | 3 | 1 | 789 | 6q27 chr6:165,740,776-166,075,588 |
PDE11A | 14 | 5 | 489–933 | 2q31.2 chr2:178,492,797-178,973,066 |
This gene annotation was provided by the Ensembl data. The Ensembl includes both automatic annotation and manual curation. All Ensembl transcripts are based on experimental evidence, and thus the automated pipeline relies on the mRNAs and protein sequences deposited into public databases from the scientific community. The manual curation occurs through the merging of the automated method with the Consensus Coding Sequence (CCDS) in a unique transcript. However, the number of coding transcripts used to assemble this table only refers to the information acquired through the manual curation because it provides a better confidence in the actual number of known isoforms. Furthermore, this information may also explain some missing known isoforms that were not called by the automated method and are known by the scientific community.
Based on GRCh37/h19.
A. PDE1
Human PDE1A, PDE1B, and PDE1C genes are located on different chromosomes: 2q32.1, 12q13, and 7p14.3, respectively. Each of the three PDE1 genes encodes unique variants. To date, about 10 protein products for PDE1A, two for PDE1B, and five for PDE1C have been described. The distinguishing feature of the PDE1 family (4, 71) is its regulation by Ca2+/CaM. The overall structure of PDE1 is shown in Figure 3A. All PDE1 enzymes hydrolyze both cAMP and cGMP, although the affinity for each nucleotide varies by isoform, with PDE1A and PDE1B exhibiting a higher affinity for cGMP than cAMP, and PDE1C having similar affinities for cAMP and cGMP. The association of one Ca2+/CaM complex to binding sites in the PDE1 monomer stimulates cyclic nucleotide hydrolysis, with different magnitudes according to the splice variant and the N-terminal sequence (4, 71–74).
PDE1A, PDE1B, and PDE1C isoforms are differently distributed in cells and may have different functional roles in cardiovascular, nervous, and immune systems; testis; and sperm. For instance, PDE1A is highly expressed in the brain and spermatozoa (72) and also in the kidney, liver, pancreas, and thyroid gland (75, 76). PDE1B is present in the brain, heart, and skeletal muscle (77). PDE1C is mainly expressed in brain and heart (78, 79), in olfactory epithelium (80), and in the testis (74).
In humans, PDE1C has been demonstrated to be a major regulator of smooth cell proliferation, with little or no expression in quiescent smooth muscle but increased expression in proliferating smooth muscle cells in culture and in smooth muscle cells isolated from atherosclerotic lesions (81). In olfactory epithelium, it regulates cAMP signals in response to odorant stimulation (80). PDE1B is expressed in T-lymphocytes and modulates the allergic response by regulating IL-13 function (82).
Pde1b-knockout mice show increased locomotor activity and deficits in spatial learning and memory (83). PDE1B may also contribute to other neuronal functions because it is expressed in multiple central nervous system regions. No reports are available for PDE1A or PDE1C animal models.
PDE1 is a possible therapeutic target in dementia and memory loss (84, 85). Specific PDE1 inhibitors, eg, IC224 and IC229, however, are not commercially available (79, 86). Recently, vinpocetine, a PDE1 inhibitor, has been used in animal experiments related to the modulation of certain behaviors and cognitive functions (87, 88).
B. PDE2
A single PDE2A gene (chromosome 11q13.4) gives rise to three PDE2 variants, the soluble PDE2A1 (89), and the membrane-associated PDE2A2 and PDE2A3 isoforms (90, 91). All PDE2 isoforms share the same C-terminal sequence but differ in their N-terminal sequences. Two distinct GAF domains, GAF-A and GAF-B, are present in the N-terminal portion of PDE2A (Figure 3B) and have distinct functions in dimerization and in cGMP binding, respectively (92). PDE2 family members, which exhibit higher affinity for cGMP than cAMP (93), are also referred to as cGMP-stimulated PDEs. Their catalytic activities are allosterically stimulated by cGMP binding to the PDE2 GAF-B domain (94). In the presence of cGMP, hydrolysis of cAMP by PDE2 is markedly increased. Thus, as discussed above (Figure 8), in response to elevated cGMP (4), a major feedback role is attributed to PDE2 by its inducing negative cross talk between cGMP and cAMP pathways (95).
Mechanisms other than cGMP binding to PDE2 GAF-B may also be important in PDE2 function. It has been shown that AIP, a crucial component of the aryl hydrocarbon receptor (AhR) complex, is a PDE2A-interacting protein (96). Binding of PDE2A to AIP inhibited the nuclear translocation of AhR, an important function of the AIP target in Hepa1c1c7 hepatocytes (97). Thus, an important regulatory role has been attributed to cyclic nucleotides in AhR trafficking, and PDE2A, through binding to AIP, might be specifically important for AhR mobility in the cytosol. AIP also binds to PDE4A5, as will be discussed further in Section III.D.
PDE2 is expressed in a wide variety of human tissues, including heart, liver, adrenal gland, platelets, brain, endothelial cells, neurons, and macrophages (64–67, 98–101). PDE2 regulates either cAMP or cGMP, depending on the cell type in which it is expressed. One of the first specific functions attributed to PDE2A involved down-regulation of aldosterone production in adrenal zone glomerulosa cells. ACTH stimulates, along with cortisol, aldosterone secretion through activation of cAMP. In bovine adrenal glomerulosa cells, elevation of cGMP induced by atrial natriuretic peptide activates PDE2A, which, in turn, rapidly decreases the ACTH-stimulated cAMP (102), resulting in down-regulation of aldosterone secretion. In cardiac myocytes and platelets, NO and nitrovasodilators increase cGMP via activation of guanylyl cyclase. In the heart, cGMP-induced activation of PDE2A leads to increased hydrolysis of cAMP, inhibition of cAMP-stimulated L-type Ca2+ current, and suppression of myocardial inotropy (47, 103). In platelets, cGMP activates PDE2 and reduces cAMP (104), thus blocking effects of cAMP on platelet aggregation. In both cardiac myocytes and platelets, PDE2 effects are counterbalanced by cGMP-induced inhibition of PDE3, and thus, together, the two PDEs mediate opposing regulatory effects on cAMP hydrolysis (4).
Macrophages also highly express PDE2 (105, 106), and it has been reported that PDE2 is involved in differentiation of monocytes to macrophages (98). In rat peritoneal macrophages, expression of the enzyme correlates with the activation state of cells (107). PDE2 is thought to serve not only as the primary regulator of cGMP, but also to regulate cAMP in response to cGMP in macrophages (4). Furthermore, PDE2 plays a role in endothelial permeability and proliferation, under pathological conditions. In cultured human endothelial cells, PDE2A activity was stimulated by TNF-α, and inhibition of PDE2 activity significantly altered the barrier function of endothelial cells (108). In brain neurons, PDE2 functions predominantly as a regulator of cGMP (4), and inhibition of PDE2 leads to activation of neuronal NOS, which in turn improves memory in older animals (109).
Although, among the PDE families, the compound EHNA is a relatively selective inhibitor of the PDE2 family, it also inhibits adenosine deaminase (110–113). Several selective PDE2 inhibitors have been developed and, although none of them have been tested in humans, animal studies have suggested promising effects of these compounds in the regulation of endothelial permeability, learning, and memory, especially BAY-60–7750, which improves learning in animal models (114). Another compound, PDP, was found to inhibit thrombin-induced edema formation in mouse lung (108). Recently, Morita et al (115) characterized PDE2A in human malignant melanoma pseudomyxoma peritonei cells and discovered mutations in pseudomyxoma peritonei PDE2A2. The authors suggested that the PDE2A mutations were associated with down-regulation of cyclin A and induction of G2/M arrest, thus raising the possibility that targeting PDE2A2 might be useful in treating malignant melanoma.
C. PDE3
Two genes—PDE3A (located on chromosome 12p12 and encoding three variants, PDE3A1, PDE3A2, and PDE3A3) (116, 117) and PDE3B (on chromosome 11p15.1, with no splice or other alternative start variants identified) (4)—constitute the PDE3 family. Although PDE3 hydrolyzes both cAMP and cGMP, the rate of hydrolysis is 10-fold greater for cAMP than for cGMP, whereas the affinity for cGMP is significantly higher. Thus, cGMP behaves as a competitive inhibitor of cAMP hydrolysis by PDE3 (118). PDE3A and PDE3B isoforms display high structural homology and very similar kinetic properties. Both contain a 44-amino acid insert in the catalytic domain (unique to PDE3 family) and N-terminal hydrophobic membrane association regions (Figure 3C) (4, 7). PDE3 family members, which contain multiple phosphorylation sites in their N-terminal region, can be regulated by phosphorylation (PKA, protein kinase B [PKB], protein kinase C) in response to hormonal stimulation (11).
PDE3A is expressed in heart, vascular and placental smooth muscle, platelets, and corpus cavernosum smooth muscle, whereas PDE3B is more highly expressed in cells and tissues important in regulation of energy homeostasis and glucose and lipid metabolism, including adipose tissue, liver, pancreatic β-cells, and hypothalamus (4, 119). PDE3B is also expressed in the cardiovascular system but at much lower levels that PDE3A (120). In rats, PDE3A transcripts are abundant in the myocardium, smooth muscle, epithelium, megakaryocytes, and oocytes, whereas PDE3B is expressed in white and brown adipose tissues, hepatocytes, renal collecting duct epithelium, spermatocytes, and embryonic neuroepithelium (121).
Studies with PDE3A and PDE3B knockout mice demonstrated that PDE3A is the major PDE3 subtype responsible for effects of PDE3 inhibitors on platelet activation/aggregation, basal myocardial contractility, and vascular smooth muscle proliferation/remodeling (59, 122, 123). PDE3B, through interaction with PI3K, is also thought to be important for the regulation of cardiac inotropism (124). The specific roles of PDE3A and PDE3B in regulation of smooth muscle contractility and function are not known (120, 125). In oocytes, PDE3A is the predominant cAMP hydrolyzing PDE. Female PDE3A-deficient mice are infertile because in oocytes lacking PDE3A, increased cAMP/PKA signaling blocks activation of MPF (Cdc2/cyclinB complex) and thus prevents meiotic progression, oocyte maturation, and fertilization (45).
PDE3B, on the other hand, plays a crucial role in the regulation of energy homeostasis. Pde3b knockout mice exhibit a complex phenotype, exhibiting some signs of insulin resistance, with increased liver triglyceride content and expression of key gluconeogenic enzymes, and reduced ability of insulin to lower hepatic glucose output and to inhibit lipolysis (126). On the other hand, the knockout mice exhibit increased lean mass and reduced amounts of white adipose tissue, as well as increased serum adiponectin and potentiation of insulin secretion. Isolated pancreatic islets from knockout mice exhibit potentiation of glucose-mediated as well as glucagon-like peptide 1/cAMP-mediated insulin secretion, consistent with stimulatory effects of PDE3 inhibitors on insulin secretion in model cell systems (126). Furthermore, Pde3b transgenic mice that specifically overexpress PDE3B in β-cells demonstrate an impaired acute insulin response to iv glucose loads and reduced insulin secretion in islets in vitro (127). PDE3B overexpression in β-cells induces diabetes-like symptoms in response to a high-fat diet, suggesting that pancreatic cAMP might be an important regulator in delaying high-fat diet-induced insulin resistance (128). Noteworthy, in a Japanese study, identified polymorphisms in the 5′ flanking region of the PDE3B gene were not correlated with susceptibility to type 2 diabetes (129).
One characteristic of PDE3 isoforms is their capacity to be phosphorylated and activated in response to agents that increase cAMP and to insulin, IGF-1, leptin, and IL-4 in different cells (130). Phosphorylation/activation of PDE3A or PDE3B by cAMP/PKA represents a feedback type regulation of cAMP signaling by attenuation of the magnitude and duration of cAMP signals. Protein kinase C has also been reported to phosphorylate/activate PDE3A (131).
In adipocytes, insulin-induced serine phosphorylation and activation of membrane-associated PDE3B, via insulin receptor substrates/PI3K/PKB signaling, is a major mechanism whereby insulin acutely antagonizes catecholamine-induced lipolysis and release of fatty acids (86, 130). Regulation of this important physiological action of insulin involves phosphorylation/activation of PDE3B by PKB, which leads to increased degradation of cAMP and consequent lowering of PKA activity, net dephosphorylation of hormone-sensitive lipase, and reduced lipolysis. PI3K/PKB signaling seems to be a common mechanism for activation of both PDE3B and PDE3A isoforms in producing effects that are counter-regulatory to effects of cAMP. Activation of PDE3B by IGF-1 and leptin in pancreatic β-cells and by leptin in hepatocytes and the hypothalamus is important in the inhibitory effects of IGF-1 and leptin on glucagon-like peptide 1 and cAMP-mediated insulin secretion and the inhibitory effects of leptin on cAMP/PKA-induced glycogenolysis, appetite, and feeding behavior. Activation of PDE3A by leptin and thrombin in platelets and of PDE3 (most likely a PDE3A homolog) by insulin/IGF-1 in Xenopus oocytes is important in the stimulatory effects of insulin and IGF-1 on oocyte maturation and of leptin and thrombin on platelet activation (130).
Although PDE3 inhibitors have been useful in basic research studies to help define specific physiological roles of PDE3 isoforms, the lack of selective PDE3A or PDE3B inhibitors has hindered progress in defining roles of the individual subfamilies and in improving selectivity in clinical applications. Several therapeutic applications of PDE3 inhibitors are discussed in Section IV.
D. PDE4
PDE4, the largest and one of the earliest discovered PDE families, specifically hydrolyzes cAMP with high affinity. Four genes, PDE4A, PDE4B, PDE4C, and PDE4D (on chromosomes 19p13.2, 1p31, 19p13.11, and 5q12, respectively), generate at least 20–25 protein variants by alternative splicing (54, 132, 133). These proteins are categorized into three N-terminal variant groups (long form, short form, and super-short form) according to the presence or absence of the unique signature N-terminal UCR1 and UCR2 domains (134, 135). Long PDE4 isoforms contain both UCR1 and UCR2, short PDE4 forms lack UCR1, and super-short isozymes contain only half of UCR2. Ligand region 1 connects UCR1 to UCR2, and ligand region 2 connects UCR2 to the catalytic domain (Figure 3D) (136). UCRs are involved in regulation of PDE4 enzymatic activity (137–139) and also participate in PDE4 dimerization (140). UCR1 and UCR2 form a regulatory module that is disrupted by PKA phosphorylation of UCR1, leading to activation of PDE4 (137). The C-terminal end of the catalytic domain of all PDE4 isoforms, except those from the PDE4A subfamily, can be phosphorylated by ERK (141). ERK-induced phosphorylation inhibits PDE4 long forms but activates short forms (8, 141). Erk-induced regulation of PDE4 may be important in the cross talk between cAMP/PKA- and ERK-signaling pathways that may be involved in changes in the PDE4 isoform profile during macrophage differentiation and in memory processes (142, 143).
PDE4 expression is ubiquitous (144, 145). In human brain, PDE4A expression is relatively high, and the tissue distribution is variant-specific (146). Heart and small intestine also express PDE4A (147, 148). Immune cells highly express PDE4, especially PDE4B and PDE4D isoforms (149, 150). PDE4C expression is ubiquitous but has been reported to be low in the lung and absent in blood (145).
The PDE4 family modulates β2-adrenergic responses in pulmonary smooth muscle and cardiac tissue, in part, through interactions with β-arrestin (151). Adrenergic stimulation (with activation of ERK signaling mediated by PKA) causes recruitment of a β-arrestin, which binds to the catalytic domain of PDE4 (151). The β-arrestin/PDE4 complex is recruited to the activated β2-receptor where it contributes to cAMP degradation (thus constituting a negative-feedback regulation), inhibition of PKA activity, and modulation of β2-receptor switching from Gs to Gi signaling (152–154). PDE4 interaction with the protein mAKAP, through the N-terminal region of PDE4, is involved in the control of local cAMP and normal myocardial functioning, as well as in the development of myocyte hypertrophy (54, 155). Recently, an association between PDE4D polymorphisms and predisposition for stroke, especially the carotid and cardiogenic forms that are related to atherosclerosis, was observed in Icelanders (156), but attempts to replicate these data have yielded variable results (157), suggesting that the association might be restricted to specific populations or, in fact, be linked to a completely different gene (158).
In the heart, PDE4D interacts with the sarcolemmal RyR. Recent reports suggest that senescent Pde4d knockout mice develop progressive cardiomyopathy and accelerated heart failure after myocardial infarction (60). In this setting, the reduced PDE4D activity would result in increased PKA-mediated phosphorylation of the RyR, rendering the channels “leaky” and contributing not only to cardiac dysfunction but also to exercise-induced arrhythmia and sudden death (60, 159). These findings shed light on the potential adverse cardiac effects that PDE4 inhibitors may have on chronic treatment of asthma and stroke, as we discuss in Section IV.
Regulation of compartmentalized cAMP signaling by β-arrestin/PDE4 complex is considered to be crucial to T-cell activation (160). Indeed, studies in PDE4B knockout mice have demonstrated an important role for this isoform in regulation of immune cells (161, 162). Pde4d knockout mice exhibit impaired airway contractile responses induced by cholinergic stimulation and little or no airway hyperreactivity induced by exposure to allergen, supporting an important role for PDE4D in cholinergic airway responsiveness and development of airway hyperreactivity (163, 164). PDE4B along with PDE4D was also found to be required for neutrophil recruitment in a model of lung injury induced by endotoxin inhalation (161). Although only a few reports on PDE4A knockout mice are available, it is believed that no obvious phenotype exists in cardiac or immune systems (165).
All PDE4 isoforms are expressed in the normal pituitary and also in GH-secreting pituitary adenomas (166, 167). Interestingly, PDE4C and PDE4D expression and activity were demonstrated to be significantly higher in GH-secreting tumors carrying gsp oncogene. This phenomenon probably represents a mechanism able to counteract, at least in part, the oncogenic potential of gsp mutations (167). As mentioned previously, PDE4A5 interacts with AIP, providing further evidence for a functional connection between cAMP signaling and the AhR pathway. Heterozygous mutations in the AIP gene predispose to pituitary tumorigenesis (168–170) and, in a yeast two-hybrid assay, it was found that AIP reversibly inhibited the activity of PDE4A5 and increased its sensitivity to the PDE4-specific inhibitor rolipram (171). It is not clear how the genetic defects in AIP induce tumorigenic effects, but this protein is thought to act as a tumor suppressor, and it has been shown that mutations in AIP gene not only disrupt AIP function in the AhR complex but also compromise its ability to bind to the interacting partner PDE4A5 (172). It has been suggested that cyclic nucleotide signaling is required for an adequate transcriptional response of the AhR complex (96), and a disequilibrium in this coordinated mechanism may be involved in the predisposition to pituitary tumorigenesis.
More recently, PDE4D mutations were found in patients with acrodysostosis (a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature) (173–175). Interestingly, mutations in PRKAR1A have also been found in this disease (176–178). The role of PDE4D in bone biology has not been investigated, although one might speculate that it relates to the regulation of cAMP signaling and the known effects of PRKAR1A mutations and PKA signaling in osteoblasts (179, 180).
As will be discussed in Section IV.C, the therapeutic potential of PDE4 inhibitors has long been recognized, especially as anti-inflammatory agents, and recently roflumilast, a selective PDE4 inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) as therapy for chronic obstructive pulmonary disease (COPD).
E. PDE5
PDE5 specifically hydrolyzes cGMP (181–183) and is encoded by a single PDE5A gene (chromosome 4q27), which gives rise to three N-terminal variants (PDE5A1, PDE5A2, and PDE5A3) in humans (184–187). PDE5A contains two GAF domains: GAF-A and GAF-B (Figure 3E). GAF-A is responsible for allosteric binding of cGMP, which promotes PDE5 phosphorylation, increasing both catalytic activity and cGMP-binding affinity (188, 189).
PDE5 transcripts are relatively highly expressed in certain human tissues, especially in smooth muscle, including the vascular tissues of the penis, and also in platelets (183–187). PDE5A1 and PDE5A2 are widely expressed, whereas specific expression of PDE5A3 in smooth and/or cardiac muscle has been suggested (185).
Studies with PDE5 inhibitors have been very useful as research tools for elucidating the physiological functions of PDE5 in various tissues. The most established function of PDE5A is in the regulation of vascular smooth muscle contraction through regulation of cGMP and intracellular Ca2+, especially in the lung and penis (4). In the corpus cavernosum of the penis, PDE5 inhibition enhances relaxation of smooth muscle induced by NO and cGMP, and thereby stimulates penile erection (190–192). Similarly in the lung, PDE5 inhibition opposes smooth muscle vasoconstriction (4). PDE5 is also thought to be important in the regulation of platelet aggregation (193, 194) and has been implicated in enhancing learning and memory (195). In the heart, PDE5 inhibition may offer protection against ischemia/reperfusion injury (196–198) and in certain heart failure animal models (199).
Special notoriety was attributed to this PDE family after the development of the potent and selective PDE5 inhibitor sildenafil and its successful use in the treatment of erectile dysfunction (190–192). New therapeutic fields for PDE5 inhibitors have been opened, including pulmonary hypertension (200), high-altitude mountain sickness (201), cardiovascular diseases (196), and memory dysfunctions (202), as we discuss in Section IV.
F. PDE6
PDE6 family members, also known as photoreceptor PDEs, specifically hydrolyze cGMP. Genes located on chromosomes 5q31.2–34, 4p16.3, and 10q24, respectively, encode the three catalytic subunits of the three PDE6 isoforms A, B, and C. PDE6A and PDE6B are expressed in rods, and PDE6C is expressed in cones. In addition, PDE6G (chromosome 17q25) and PDE6H (chromosome 12p13) genes encode the inhibitory subunits that modulate the activity and intracellular localization of these enzymes (Figure 3F). PDE6 isoforms are highly expressed in the photoreceptor outer segments of the mammalian retina (203–205) and in the pineal gland (206).
cGMP plays a central role in visual transduction (3). In the dark, photoreceptor cGMP concentrations are elevated, and cGMP binds to and opens photoreceptor cGMP-gated channels (CNGCs), allowing influx of Ca2+ and Na+ (dark current), which depolarizes photoreceptor cell membranes. The PDE6 activation cascade is initiated when a photon of light is absorbed by rod or cone photoreceptors. Immediately, the G protein transducin, activated by GDP-GTP exchange, activates PDE6 catalytic subunits by displacing the PDE6 inhibitory subunit from the active site, thus stimulating cGMP hydrolysis. The decrease in cGMP causes deactivation and closure of the photoreceptor CNGCs in the nearby plasma membrane, which results in hyperpolarization of the photoreceptor cell membrane, converting the light signal into an electrical signal and initiating the visual transduction process (207).
PDE6 was the first PDE in which genetic mutations were found to cause disease. Several forms of night blindness (13, 208) and retinitis pigmentosa (14, 209, 210) were mapped to different locations in PDE6 genes. In the presence of PDE6 mutations, chronic elevation of photoreceptor cGMP can lead to progressive dysfunction and cell death (4, 211, 212). Indeed, in animal models with defective PDE6 enzymes, increased cGMP accumulation in photoreceptor cells leads to cell death (211). In a recent description of new PDE6A mouse models for recessive retinitis pigmentosa, significantly different rates of degeneration of murine photoreceptor cells were observed, indicating allelic variation and structure-function relationships, and suggesting that the variation of the disease phenotype may be dependent upon the presence of a particular allele (213).
Sildenafil, vardenafil, and udenafil inhibit PDE6, with lower affinities than those for PDE5A, but this inhibition has been suggested to be the source of some of the visual side effects reported with sildenafil usage (4).
G. PDE7
The PDE7 family (214) is highly selective for cAMP (214–216) and comprises two genes, PDE7A (chromosome 8q13) and PDE7B (chromosome 6q23–24). Alternative splicing of PDE7A gives rise to PDE7A1, PDE7A2, and PDE7A3 (215, 217). Four alternative splice variants for PDE7B have been identified with mRNA, but endogenous PDE7B proteins have not been detected (218–220). PDE7A1 is a bifunctional protein, in the sense that, in addition to its cAMP hydrolytic activity, it inhibits PKA activity by interacting directly with the catalytic subunit of PKA via its N-terminal domain (221). There is no known regulatory domain in the N-terminal region in this family (Figure 3G).
PDE7A1 is expressed in a wide variety of immune cells (95, 215, 222), and T-lymphocyte activation has been proposed to be linked to PDE7A activity (223). However, PDE7A knockout mice have been reported to show normal in vitro and in vivo T-cell functions (224). Thus, the role of PDE7 in T-lymphocyte activation and function remains unclear (225). It has been recently shown that PDE7B is activated through the cAMP/PKA/CREB pathway in striatal neurons, suggesting that PDE7B might play a role in memory function and also provide a therapeutic target in Parkinson's and Huntington's diseases (226). Indeed, studies have shown that some recently described PDE7 inhibitors may play a role in the treatment of neurological diseases in mouse models (227, 228). PDE7 expression is also considered to be both a prognostic indicator of the severity of chronic lymphocytic leukemia and a promising therapeutic target in this disease (229). Clinically effective inhibitors, however, are not available. PDE7A2 is also expressed in skeletal and cardiac muscles (215).
Due to its high expression in lymphocytes and immune/inflammatory cells (95, 215, 222), PDE7A has been considered as a pharmacological target for inflammation (225), but no PDE7 inhibitors have achieved success in clinical applications.
H. PDE8
PDE8 specifically hydrolyzes cAMP with the highest affinity among all PDEs (230, 231). The PDE8 family consists of two highly homologous genes, PDE8A (chromosome 15q25.3) and PDE8B (chromosome 5q13.3). Five splice variants have been identified for PDE8A (PDE8A1 to PDE8A5) (232) that are expressed in a variety of tissues with highest expression in testis and T-cells (217). Five variants for PDE8B (PDE8B1 to PDE8B5) are known (11). PDE8 enzymes contain N-terminal region REC and PAS (233–235) domains, the regulatory functions of which are unknown (Figure 3H). Some splice variants lack these domains.
Significant new information regarding physiological roles of PDE8 has come from studies with PDE8A and PDE8A knockout mice, isolated cell preparations (cardiac myocytes, Leydig cells, adrenal zona fasciculata cells), and PDE8 inhibitors, especially the PDE8-selective inhibitor, PF-04957325. For example, PDE8A is expressed in human and mouse hearts (231); studies in isolated ventricular myocytes from PDE8A knockout hearts have suggested that this enzyme regulates the excitation-contraction coupling cycle (236).
Both PDE8A and PDE8B are expressed in adrenal zona fasciculata cells and testicular Leydig cells. Recent studies suggested that although PDE8A and PDE8B regulate distinct (but overlapping) cAMP pools to regulate basal rates of steroidogenesis, maximal rates of steroid production require combined inhibition of PDE8A and PDE8B (with PF-04957325), as well as inhibition of PDE4 (237, 238).
A possible role for PDE8A in T-cell activation has been suggested (4), and PDE8 has also been reported to regulate lymphocyte chemotaxis and adhesion (239, 240).
PDE8A is also expressed in the ovary, and it was found that Leydig cells from mice with a targeted mutation in the Pde8a gene are sensitized to the action of LH in terms of T production (241–243). Based on the hypothesis that reduced PDE8A activity or expression would contribute to excessive ovarian androgen production in polycystic ovary syndrome (PCOS), PDE8A was recently evaluated as a PCOS candidate gene (244). The polymorphisms found were not associated with PCOS or T serum levels, suggesting that genetic variants of PDE8A may not contribute to PCOS in the studied population (244).
PDE8B is more widely expressed than previously thought, both in human and mouse tissues (245). PDE8B1 is the most abundant variant in the thyroid gland (246), whereas PDE8B1 and PDE8B3 are equally expressed in the placenta. PDE8B was found to be expressed in the normal and hyperplastic human adrenal cortex and in the adrenal gland of newborn mice, and it is also widely expressed in other tissues (245).
PDE8B mutations have been associated with genetic forms of adrenal hyperplasia. In the first study in which the genetic loci harboring PDE and other cAMP-signaling pathway genes were genotyped in patients with adrenal disease, mutations in PDE11A were associated with a predisposition to micronodular adrenocortical hyperplasia (247). In a more recent study, the PDE8B coding regions were sequenced in 20 patients with hypercortisolism due to adrenocortical hyperplasia, who were negative for variants of other known causative genes, such as PRKAR1A and GNAS (15). A single base substitution (c.914A>C) was found in a young girl who presented with Cushing's syndrome starting at the age of 2 years. This mutation affects a residue (His305Pro) highly evolutionarily conserved and located at the end of the PAS domain, which seems to impair PDE8 catalytic activity (15). As mentioned above, PDE8B seems to regulate adrenal and testicular steroidogenesis: pde8b knockout mice were reported to develop adrenocortical hyperplasia and Cushing's syndrome (238). Taken together, these results suggest that PDE8B might be another PDE gene (in addition to PDE11A, as discussed in Section K) linked to isolated micronodular adrenal disease. In a recent study of the transcriptome of cortisol-producing tumors, PDE8B expression was found to be strongly and positively associated with cortisol secretion (248). These observations, along with additional PDE8B mutations in patients with other adrenocortical tumors (15, 249), make PDE8B a candidate causative gene for adrenocortical lesions linked to cAMP-signaling pathways and possibly other endocrine tumors, especially in cAMP-sensitive tissue.
A strong association between alleles containing six polymorphic variants in the PDE8B promoter and the levels of circulating TSH has been recently reported. This suggests a primary effect of PDE8B variants on cAMP levels in the thyroid, perhaps responsible for affecting the production of T4, T3, and its feedback regulation (250, 251).
PDE8B expression was found to be absent in the normal pituitary gland but detectable in a series of GH-secreting pituitary adenomas. Similar to PDE4, higher mRNA levels are seen in the tumors bearing the gsp oncogene (167).
Although there is little or no expression of PDE8A in the brain, PDE8B (with PDE8B3 as the most abundant variant [252]) is relatively highly expressed in the hippocampus, ventral striatum, and cerebellum. The behavioral phenotype of the PDE8B knockout mouse is complex, with enhancement of spatial memory, contextual fear, and motor coordination, as well as a reduction in age-induced decline in motor coordination. Basal anxiety levels, however, were increased in PDE8B knockout mice. Thus, although selective inhibition of PDE8B might improve cognition and motor function, effects on anxiety levels may present significant side effects (252, 253).
Selective PDE8 inhibitors have recently been developed (254), and the above findings suggest that these inhibitors might have important applications in endocrine diseases, and possibly other diseases.
I. PDE9
PDE9 isoforms specifically hydrolyze cGMP with the highest affinity among all PDE families (255, 256). Twenty-one splice variants arise from the single PDE9A gene (chromosome 21q22.3) (257). Despite this high number of mRNA transcripts, only PDE9A1 and PDE9A6 (originally named PDE9A5) proteins have been shown to be expressed and were characterized (258). PDE9A mRNA is likely to undergo post-transcriptional regulation because its 5′-untranslated region contains a GC-rich region that can fold on itself (4). The amino acid sequence of the PDE9 catalytic domain has low homology to the other PDEs, which may explain the insensitivity of PDE9A1 to most PDE inhibitors, including 1-methyl-3-isobutylxanthine (IBMX) (255, 256, 259). No GAF domains or other regulatory sequences have been identified in the PDE9A1 N-terminal region (Figure 3I) (11, 259).
Human PDE9A mRNA is expressed in the spleen, small intestine, and brain. PDE9A protein expression is highly conserved among species and is widely distributed throughout the rodent brain, with the highest relative expression in Purkinje neurons and cerebellum (260, 261). Little is known about the function(s) of PDE9 in brain (or anywhere else for that matter). The pattern of PDE9A expression in rat brain closely resembles that of soluble guanylyl cyclase, suggesting a possible functional association in the regulation of cGMP levels that may play a role in behavior, cognition, and learning (260, 261). In pde9a knockout mice, cGMP (not cAMP) levels were increased in brain cortex, hippocampus striatum, cerebellum, and cerebrospinal fluid; in wild-type mice, the PDE9A-selective inhibitor PF-4181366 increased cGMP in the same brain regions as well as in the cerebrospinal fluid (262). Furthermore, PDE9A genomic location maps to a region containing genes involved in several neurological diseases, including bipolar disorder (263), and recently, a PDE9A-specific inhibitor, BAY 73–6691 was demonstrated to improve learning and memory in rodents (263–265).
J. PDE10
PDE10 enzymes (266–268) are encoded by a single gene, PDE10A (chromosome 6q26). At present, two major variants, PDE10A1 and PDE10A2, and several minor PDE10A variants have been described in humans (11). PDE10 isoforms contain two GAF domains and hydrolyze both cAMP and cGMP, with a higher affinity for cAMP than cGMP. In contrast to PDE3 (the so-called cGMP-inhibited cAMP PDE), PDE10 may function in vivo as a cAMP-inhibited cGMP PDE (4). Little is known about the regulation of PDE10 enzymatic activity, and although it has been reported that cAMP binds to one or more of the GAF domains of the enzyme (Figure 3J) (269), this interaction does not induce allosteric activation of PDE10 catalytic activity.
PDE10A is mainly expressed in the brain, with the highest expression in the striatal area, but it is also present in the cerebellum, thalamus, hippocampus, and spinal cord (266–268, 270, 271), as well as in the testis, especially in the developing spermatocytes (266, 270). PDE10 is also expressed in the thyroid and pituitary gland, but the physiological functions of the enzyme in these tissues are still unknown.
Dysregulation of PDE10A is thought to be associated with the progressive neurodegenerative Huntington's disease because PDE10A2 mRNA decreases before the onset of motor symptoms in the striatal region of brains from transgenic Huntington's disease mice (272, 273). Chronic inhibition of PDE10A (using PDE10 knockout mice or by chronic administration of a PDE10A-selective inhibitor, TP-10, to wild-type mice) altered expression of overlapping striatal genes involved in signaling pathways implicated in Huntington's disease, suggesting that PDE10 inhibitors might provide protective effects in models of Huntington's disease (274). PDE10A knockout mice also show decreased exploratory activity and delayed acquisition of conditioned avoidance behavior (275). Administration of the PDE10A inhibitors, papaverine and MP-10, produced beneficial effects in several murine and rat antipsychotic models and increased social behavior. In these studies, PDE10A inhibitors were found to improve dopaminergic and glutamatergic dysfunction thought to be associated with the schizophrenia phenotype (275, 276). Thus, selective PDE10 inhibitors (277) and dual PDE2/PDE10 inhibitors (278, 279) may be effective in the treatment of schizophrenia and neurocognitive disorders (280). A role for PDE10 in modulating striatonigral and striatopallidal pathways has also been suggested, raising the possibility that PDE10 could be a molecular target for the treatment of psychiatric disorders (281), as we discuss in more detail in Section IV.
K. PDE11
PDE11, the most recently discovered PDE family (281, 282), is encoded by only one gene, PDE11A (chromosome 2q31.2). Four different variants (PDE11A1–4), with different amino termini due to distinct transcriptional start sites, have been identified (282–285). PDE11 exhibits dual substrate specificity and hydrolyzes cAMP and cGMP with similar affinities. Its catalytic site is more similar to PDE5 than to PDE10A (282). Only PDE11A4 contains two complete GAF domains (Figure 3K), and although the GAF function in PDE11 remains to be established (285), the N-terminal truncations in PDE11A1, PDE11A2, PDE11A3, and PDE11A4 GAF domains affect catalytic activity (4, 11), with maximum velocity of enzyme of PDE11A4 nearly 100-fold greater than that of PDE11A1.
In humans, PDE11A is relatively highly expressed in skeletal muscle and prostate; high-to-moderate expression is seen in testis, pituitary gland, heart, kidney, and liver (in that order) (282, 286). Among PDE11A variant proteins, only PDE11A4 protein has been clearly detected in human tissues by immunohistochemical analysis (287), with expression demonstrated in prostate, Leydig and spermatogenic cells of the testis, kidney, adrenal, colon, and skin epidermis (288).
Little is known about the function of PDE11A. In mouse brain, in situ hybridization, quantitative real-time PCR, and Western immunoblotting indicated that PDE11A expression was restricted primarily to the hippocampal area. PDE11A knockout mice exhibited deficiencies in social behaviors, open field hyper-reactivity, and increased sensitivity to the glutamate-N-methyl-D-aspartate receptor antagonist MK-801, all suggestive of subtle disease-related phenotypes (288, 289).
Given these phenotypic changes in the pde11a knockout mouse, in a prospective study, 284 patients with the diagnosis of major depressive disorder (MDD) were genotyped for polymorphisms in PDE genes (290). Significant associations between PDE11A variations and both the diagnosis of MDD and remission in response to antidepressants were observed, suggesting a potential role for this enzyme in central nervous system function and in the pathophysiology of MDD (290). However, another study in depressed patients failed to show significant evidence for the association between PDE11A variant alleles and antidepressant outcome (291).
As previously mentioned, a genome-wide study was recently performed to search for genes conferring predisposition to micronodular adrenocortical hyperplasia, leading to Cushing's syndrome in childhood (247). In this study, the chromosomal locus harboring the gene encoding PDE11A was linked to the disease. Inactivating mutations of PDE11A were associated with micronodular adrenocortical lesions in three kindreds. cAMP levels in tissue homogenates from affected individuals with PDE11A mutations were elevated, suggesting that mutations in PDE11A lead to aberrant cAMP signaling, which can be associated with the development of bilateral adrenocortical hyperplasia (247). In another study (292), a higher frequency of two PDE11A variants (R804H and R867G, located in conserved regions of the enzyme) was observed among patients with adrenocortical tumors, when compared with normal controls. These variants affected enzymatic function in vitro, with variable increases in cAMP or cGMP levels in HeLa and HEK293 cells. These results raise the possibility that PDE11A genetic defects may be associated with adrenal pathology in a wider clinical spectrum that also includes asymptomatic individuals (292).
PDE11A is expressed in both normal and abnormal adrenocortical tissues (293). In a large cohort of adrenocortical tumors, missense PDE11A variants were frequently observed (294). Increased cAMP levels and decreased PDE11A immunostaining were present in the tumor tissues harboring the missense variants, compared with tumors with wild-type PDE11A sequence (294). This result provides more evidence that somatic defects in PDE11A predispose to a variety of lesions, beyond micronodular adrenocortical hyperplasia. Furthermore, a high frequency of PDE11A variants was found in patients diagnosed with Carney complex harboring inactivating mutations in the gene encoding the regulatory subunit 1A of the protein kinase A (PRKAR1A) (295). In this study, PDE11A variants were significantly associated with the copresence of primary pigmented nodular adrenocortical disease, a type of micronodular hyperplasia, and large-cell calcifying Sertoli cell tumors, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutations (295).
PDE11A knockout mice demonstrate impaired sperm function and spermatogenesis (296), and an involvement of PDE11A activity in spermatogenesis has been suggested (297). In a recent study, the frequency of PDE11A-inactivating sequence variants was found to be significantly higher among patients with familial and bilateral testicular germ cell tumors, compared with normal control individuals, indicating a role for PDE11A variants in modifying the risk of testicular germ cell tumors (16).
Furthermore, PDE11A sequence variants were found to be significantly more prevalent in patients with prostatic cancer, compared with healthy controls, suggesting that, as in the adrenal cortex and the testicular germ cells, PDE11A-inactivating genetic alterations may play a role in susceptibility to prostate cancer (17). Novel PDE11 inhibitors were very recently described (297, 298), and one study has shown that PDE5 and PDE11 inhibition attenuated the growth of human prostate tumor xenografts in a murine model (299), providing a rationale for future studies on the potential therapeutic applications of PDE11 inhibitors in this setting (298).
Although PDE11A4 transcripts are particularly abundant in the prostate and are detected in the testis and adrenal cortex, this isoform is also present in other endocrine tissues, including the pituitary gland (282, 284, 287). Little is known about the role of PDE11A in the pituitary. A recent study identified PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls, suggesting that PDE11A genetic variations might only marginally contribute to the development of somatotropinomas (300).
IV. PDE Inhibitors
A. Overview
After the discovery that theophylline, a naturally occurring methylxanthine, inhibits PDEs (2), thousands of PDE inhibitors (a small number of which are listed in Table 4) have been synthesized, with the aim of improving potency and specificity for inhibition of the various PDEs, not only for research purposes but also for treatment of diseases (Table 4). All known PDE inhibitors contain one or more rings that mimic the purine ring in cyclic nucleotide substrates of PDEs and directly compete with cyclic nucleotides for access to the catalytic site. The early inhibitors, theophylline and IBMX (11, 301), are designated as nonspecific PDE inhibitors because they inhibit virtually all PDEs, except PDE8 and PDE9. At present, the large number of more or less selective and/or potent PDE inhibitors represents important pharmacological tools to characterize the distribution and functional role of PDEs in organs and tissues, under normal conditions or in pathological states (Table 4). Currently, the PDE3 inhibitor cilostazol (Pletal) is widely used to treat intermittent claudication, a peripheral vascular disease; and milrinone (Primacor) is used for acute therapy in refractory heart failure and to stabilize and maintain patients preparing for heart transplants. The PDE4 inhibitor roflumilast (Daliresp) has recently received FDA approval for its use in COPD. The enormously successful PDE5 inhibitors are currently used worldwide for clinical treatment of erectile dysfunction and pulmonary hypertension (302). Related compounds target other PDEs and show therapeutic promise for a number of disorders (Table 4), as we discuss in Section IV.B.
Table 4.
PDE Inhibitors
Gene Family | Inhibitor | Use in Clinical Trials | Ref. |
---|---|---|---|
PDE1 | Nimodipine | 95, 429 | |
Vinpocetine | Anti-inflammatory agent, vasodilator, nootropic for the improvement of memory, urge incontinence, low compliance bladder, acute ischemic stroke | 430–437 | |
IC224, SCH51866, 8-MeoM-IBMX, KS-505a, IC86340, IC295, dioclein, calmidazolium, phenothiazines | No | 429, 430, 435, 437, 438 | |
PDE2 | EHNA, BAY 60-7550, PDP, IC933, oxindole, ND7001, Aptosyn | No | 429, 435, 438 |
PDE3 | Olprinone | Gastric im acidosis, systemic inflammation after cardiopulmonary bypass | 439–441 |
Milrinone, cilostamide, amrinone, enoximone | Valvular disease, pulmonary hypertension, cardiac surgery | 429, 435, 436, 438, 442–446 | |
Cilostazol, K-134 | Cerebrovascular disorders, peripheral vascular disease, intermittent claudication, prevention of stroke, peripheral arterial disease, diabetes mellitus | 362, 363, 429, 447, 448 | |
Trequinsin, OPC-33540, dihydropyridazinone, lixazinone, siguazodan, SK&F 94120, CI 930, KCA-1490 | No | 429, 435–438, 449–452 | |
PDE4 | Ibudilast | Bronchodilator, vasodilator, neuroprotective effects, asthma, stroke, inhibits platelet aggregation | 435, 453–456 |
Cilomilast | Emphysema, bronchitis | 429, 438, 457, 458 | |
Mesembrine | Anticonvulsant activity, antidepressant, mental illnesses, specifically epilepsy, depression, age-related dementia, and debilitative mental disorders | 435, 459 | |
Etazolate | Alzheimer's | 436, 460 | |
Rolipram | Multiple sclerosis, MDD | 414, 429, 435, 436, 438, 461, 462 | |
Roflumilast | Chronic obstructive pulmonary disease, asthma | 429, 435, 436, 452, 457, 463 | |
Denbufylline | 436 | ||
Ro 20–1724, AWD 12281, V-11294A, SCH 351591, SB 207499, tibenelast, NCS 613, zardaverine, TVX 2706, ZK 803616, HT0712, Ariflo, RS-25344, KCA-1490, L-826,141, CDP-840, V11294A | No | 429, 435–438, 450, 452, 462, 464 | |
PDE5 | Sildenafil | Pulmonary hypertension, diabetes mellitus, endothelial dysfunction, ischemic stroke, schizophrenia, active digital ulcers, erectile dysfunction, gastroparesis, sickle cell anemia | 429, 435, 436, 438, 443, 465–469 |
Tadalafil | Benign prostatic hyperplasia, erectile dysfunction, pulmonary hypertension, prostate cancer | 435, 436, 465, 467, 470, 471 | |
Vardenafil, lodenafil, avanafil | Erectile dysfunction | 429, 435, 436, 465 | |
Dipyridamole | Erectile dysfunction, ischemia-reperfusion injury, atherosclerosis, stroke, breast cancer, rheumatoid arthritis | 436, 465, 472–474 | |
Udenafil | Erectile dysfunction, chronic obstructive pulmonary disease | 435, 436, 475, 476 | |
Zaprinast, E4021, DMPPO, CP461, MY-5445, NCX 911, DA-8159 | No | 429, 435, 436, 438, 465 | |
PDE6 | Zaprinast, dipyridamole, DMPPO, sildenafil, vardenafil | No | 429, 438 |
PDE7 | BRL 50481, IC242, BMS-586353, thiadiazoles, ASB16165 | No | 429, 435, 438 |
PDE8 | PF-04957325 | No | 429, 477 |
PDE9 | BAY 73-6691, SCH 51866, PF-04447943 | No | 429, 435, 436, 438, 477 |
PDE10 | Papaverine | Sexual dysfunction and infertility | 429, 435, 477 |
PQ-10, TP-10, MP-10 | No | 429, 435, 477 | |
PDE11 | None selective | No | 429, 435, 438 |
B. PDE5 inhibitors and their clinical use in erectile dysfunction, pulmonary hypertension, and other disorders
1. Erectile dysfunction
After sexual arousal, NO, released from the nerve endings and from vascular endothelial cells in the penis, diffuses into the smooth muscle cells of the corpus cavernosum and stimulates guanylyl cyclase to convert GTP into cGMP. This in turn activates PKG to induce phosphorylation of key regulatory effector proteins, resulting in a decrease in intracellular calcium that leads to penile smooth muscle relaxation, and, consequently, vasodilatation, an increase in blood flow into the penis, and penile erection (190, 303). PDE5, which specifically degrades cGMP, is relatively highly expressed in the corpus cavernosum, and thus PDE5 inhibitors, by blocking hydrolysis of cGMP, potentiate effects of cGMP on penile erection (190, 192, 303).
Sildenafil was the first commercially available PDE5 inhibitor, followed by vardenafil and tadalafil. Sildenafil is effective in almost every subgroup of patients with erectile dysfunction, although reduced responsiveness has been reported in diabetic patients and after prostatectomy (304). As mentioned earlier, because sildenafil and, to a lesser extent, vardenafil, slightly inhibit photoreceptor PDE6, some patients treated with these drugs experience temporary and reversible mild visual disturbances. Tadalafil slightly inhibits PDE11, but the functional consequences of this effect are unknown. The extended half-life of tadalafil provides a longer therapeutic effect than sildenafil and vardenafil (305). Adverse effects of the three agents are usually mild, including headache, flushing, and nasal congestion. No current evidence suggests that the efficacy of any one of these drugs is superior to the others (306).
Avanafil (Stendra), which acts more rapidly than other PDE5 inhibitors, was recently approved for use by the FDA. Other new PDE5 inhibitors, including udenafil and mirodenafil (both already approved for clinical use in South Korea), and lodenafil carbonate are currently under development (307–309).
Clinical trials have also investigated the potential effectiveness of sildenafil and vardenafil in the treatment of premature ejaculation, and prolongation in intravaginal ejaculatory latency time and/or an improvement in the overall perception of ejaculatory control and sexual satisfaction have been reported (310–313). In addition, a recent study showed that several family-selective PDE inhibitors, sildenafil (PDE5), milrinone (PDE3), and rolipram and Ro 20–1724 (PDE4), increase cyclic nucleotide concentrations and counteract the contraction of human seminal vesicle muscle induced by norepinephrine (314), thus supporting the notion that PDE inhibitors might be useful in treating premature ejaculation.
2. Pulmonary hypertension
PDE5 inhibitors have recently become an attractive first-line choice in the treatment of milder forms of pulmonary arterial hypertension (315). In the lung, the production of cGMP in response to NO activates PKG, which in turn decreases pulmonary artery smooth muscle cell calcium and potassium levels, leading to pulmonary artery vasodilatation, and decreased proliferation and increased apoptosis of pulmonary artery smooth muscle cells (315). Inhibition of PDE5 increases the effects of NO on cGMP accumulation, resulting in pulmonary vasodilatation and inhibition of smooth muscle growth and remodeling.
Sildenafil was approved by the FDA for treatment of pulmonary hypertension in 2005, based primarily on results from the SUPER trial (316). Sildenafil improves not only the symptoms of pulmonary hypertension, but also exercise tolerance, hemodynamics, and quality of life (316–318). Long-term data in patients receiving 80 mg three times daily for 1 year have shown sustained benefit with minimal adverse effects (317). Tadalafil was approved by the FDA in 2010, and its longer half-life of 17.5 hours compared to that of sildenafil (4 to 5 hours) allows for a once-daily dosing (319–321). Clinical benefits from therapy with tadalafil or sildenafil have been shown to be similar (317–321). Vardenafil has also shown some efficacy in the treatment of pulmonary hypertension (322, 323).
C. PDE4 inhibitors and their promising clinical uses
1. Respiratory and other inflammatory diseases
Because of the prominent effects of cAMP and PDE4 in immunomodulatory responses (324), this PDE has long been considered as a potential target in the treatment of several inflammatory diseases. Indeed, the archetypal nonselective PDE inhibitor, theophylline, has been used for treatment of asthma and COPD for over 70 years, although its narrow therapeutic ratio and the multiple potential important interactions with other drugs limit its use in these and other disorders (325).
The PDE4 inhibitor rolipram and its analogs failed in clinical trials because of their emetic effects and other gastrointestinal disturbances (326). On the other hand, roflumilast, which is a highly selective PDE4 inhibitor that does not discriminate between any of the PDE4 gene variants, has been recently approved for the treatment of COPD in the United States, Europe, and several other countries (327–331). Roflumilast is effective in reducing the frequency of exacerbations of the disease in patients with moderate or severe COPD, as shown in different clinical trials. The drug is administered once daily, and the most prevalent side effects observed in the trials were headache and gastrointestinal symptoms, such as diarrhea, weight loss, and nausea (327, 329, 330). Given that combined inhibition of PDE3 and PDE4 has shown additive and synergistic anti-inflammatory and bronchodilatory effects, attempts to develop inhaled dual PDE3/4 inhibitors for the treatment of COPD are in progress (332, 333).
Preclinical studies in models of allergic pulmonary inflammation have documented the ability of PDE4 inhibitors to inhibit two important characteristic features of asthma: the recruitment of eosinophils to the airways and bronchial hyperresponsiveness (although PDE4 inhibitors are not bronchodilators) (334–336). Indeed, clinical trials corroborate moderate benefits of PDE4 inhibitors in the treatment of asthmatic patients (334–336). In some clinical trials, PDE4 inhibitors have showed some benefit for the treatment of allergic rhinitis (337), inflammatory bowel disease (338), and psoriasis (339).
It is important to mention that, although there is reason for optimism concerning the potential therapeutic utility of PDE4 inhibitors for the treatment of respiratory diseases, it is clear that further improvements are required, especially regarding issues related to tolerability and side effects such as emesis and diarrhea (326, 329, 336). Hence, increasing our understanding of the physiological actions of PDEs, in parallel with the development of PDE inhibitors, may result in more effective therapeutic applications for PDE4 inhibitors.
2. Neurological and psychiatric disorders
PDE4 is expressed in neurons in the cerebral cortex and hippocampus, hypothalamus and striatum, dopaminergic neurons of the substantia nigra, and astrocytes (340, 341), where they are thought to be important regulators of β-adrenoceptor-stimulated cAMP signaling (342). Recently, there has been a resurgence in the study of PDE4 in neuroscience, reminiscent of the period of development of rolipram for depression (343) and Parkinson's disease (344) two decades ago (133). Indeed, PDE4 inhibitors have shown efficacy in mouse models of both depression and Parkinson's disease (344–347). PDE4 inhibition increases phosphorylation of CREB and hippocampal neurogenesis, producing antidepressant-like and memory-enhancing effects in rodents (345, 347). In addition, a recent study has shown that tofisopam, a compound with anxiolytic and antipsychotic properties, acts as an inhibitor of PDEs, with the highest affinity to PDE4A, PDE10A, PDE3, and PDE2A (348). The recent description of PDE4D allosteric modulators with reduced potential to cause emesis may facilitate the design of therapeutic approaches for Alzheimer's disease, Huntington's disease, schizophrenia, and depression (349). Many drug companies are actively developing PDE10 inhibitors as therapy for schizophrenia and other neuropsychiatric disorders, as well as to enhance cognition (350).
On the other hand, cGMP is also widely distributed in the brain. PDE2, PDE5, and PDE9 are the most prevalent PDE isozymes in the central nervous system (260, 261), where cGMP, activated by NO or by the natriuretic peptides, may play a role in the regulation of behavior and learning (114, 262), as mentioned previously. This raises the possibility of targeting cGMP-specific PDEs for the treatment of Alzheimer's disease and other neurological disorders (351).
D. PDE inhibitors and the cardiovascular system
PDE3 inhibitors, via increasing cAMP levels, enhance developed contraction and relaxation in cardiomyocytes and reduce total vascular resistance in smooth muscle. It is interesting to highlight that milrinone was the first drug approved and commercially distributed for PDE suppression (352). Initially, this pharmacological agent was developed to treat heart failure, due to the fact that PDE3A is highly expressed in the heart, and because PDE3 inhibitors were potent inotropic agents (353, 354). This information justified the development and clinical use of a number of PDE3 inhibitors, including milrinone, for the treatment of congestive heart failure. Increased mortality due to arrhythmias and sudden death has restricted the use of these drugs (355). Milrinone is, however, used as acute therapy in refractory heart failure, to stabilize and maintain patients preparing for heart transplants, and as adjunct therapy for cardiogenic shock (352). Milrinone is also used to treat persistent pulmonary hypertension (356, 357); to reduce the risk of developing low cardiac output syndrome in children after corrective surgery for congenital heart disease (358); to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (359); to improve the prognosis of patients with circulatory failure both before and after cardiac surgery (360); and to treat neonatal septic shock (361).
Cilostazol, another PDE3 inhibitor, is currently widely used as a treatment for intermittent claudication (362), and also for prevention of stroke in patients with peripheral arterial disease (363) by causing vasodilatation and anti-aggregatory effects on vascular smooth muscle and platelets, respectively (353). Cilostazol can also inhibit PDE5, which may account for some of its beneficial effects. In small trials, cilostazol has been reported to attenuate poststenting or postangioplasty restenosis (364) and to slow progression of a surrogate marker of atherosclerosis in persons with diabetes (365). This drug can also reduce plasma triglyceride levels, with a concomitant increase in high-density lipoprotein cholesterol concentrations, therefore improving the proatherogenic lipid profile in patients with type 2 diabetes (366).
Recently, there has been renewed interest in investigating the role of PDE5 inhibition in the heart (367–369). In animal models of cardiac hypertrophy and heart failure due to pressure overload, the PDE5 inhibitor sildenafil completely prevents the hypertrophic and fibrotic response caused by the increased pressure (199). Additional benefits of sildenafil have also been demonstrated in prevention/amelioration of acute ischemia-reperfusion injury (196–198). The cardioprotective effects of sildenafil are linked to various known regulators of cardiovascular function, such as NOS, mitochondrial ATP-sensitive potassium channels, and the regulator of G protein signaling 2 (367, 370–374), but the benefits in human patients await confirmation. Results from a recent clinical trial indicated that the sildenafil improved left ventricular function in heart failure patients (375).
E. PDE inhibitors and cancer
Studies of the molecular and cellular biology of cancer have revealed that various genetic and epigenetic changes, acting together, lead to the activation of signaling pathways, which sometimes ultimately result in cell proliferation and carcinogenesis. Thus, regulation of cyclic nucleotide signaling is properly regarded as one of several component pathways involved in tumor cell propagation and function. Indeed, various alterations leading to activation or inactivation of key components of cAMP and cGMP signaling pathways are observed in tumorigenesis. For instance, decreased cAMP levels are observed in chronic lymphocytic leukemia (229) and some malignant carcinoma cells (376), as a consequence of overexpression of PDEs, whereas decreased PKG expression occurs in many tumors and cancer cell lines as compared with their normal counterparts (377). Accordingly, it has been shown that elevated cellular cAMP levels can arrest growth, induce apoptosis, and attenuate cancer cell migration/growth in breast (374, 378) and colon cancer (379, 380) cells. Similarly, increasing cGMP levels inhibits growth and cell migration and induces apoptosis in human colon cancer cells (381, 382). Although further extensive investigation is needed, various reports have indicated the involvement of individual PDE enzymes in various tumor tissues, suggesting a potential role for PDE inhibitors as anticancer drugs (383).
Cell culture and preclinical studies have demonstrated promising effects of PDE inhibitors in the treatment of cancer. The PDE1 inhibitor vinpocetine inhibited cell growth in human malignant melanoma-associated antigen cells (384). PDE2 is highly expressed in endothelial cells, and the combination of PDE2 and PDE4 inhibitors blocked cell migration and proliferation (385). The PDE3-specific inhibitor cilostamide inhibited the proliferation of human malignant melanoma and squamous cell carcinoma cells (386). Inhibition of PDE4 with rolipram in brain tumor cells suppresses tumor growth and augments the antitumor effects of chemotherapy and radiation therapy (387). It was recently reported that hypoxia increased PDE4A and PDE4D in human lung cancer cell lines, and that PDE4 inhibition inhibited cell growth and hypoxia-induced vascular endothelial growth factor secretion by these tumor cells (388). Because PDE4 is thought to be involved in the regulation of cell migration (389), and PDE4 inhibitors cause profound growth arrest of chemoresistant KM12C colon cancer cells (379), these drugs may provide a novel therapeutic target for metastasis. PDE5 inhibition has been shown to augment endogenous antitumor immunity (390), and PDE5 inhibitors in combination with chemotherapy improve survival in tumor-bearing rats, compared with the animals treated with chemotherapy alone (391). Moreover, the antineoplastic drug exisulind was shown to induce apoptosis by inhibiting PDE1 or PDE2 and PDE5 (392). Inhibition of PDE7 promotes apoptosis in chronic lymphocytic leukemia (229). PDE11A is also a potential target for cancer therapies because several malignant human tissues prominently express this enzyme, including renal, prostate, colon, lung, and breast carcinoma (288). However, PDE11A-specific inhibitors are currently not available.
On the other hand, and in at least some tissues, increased cAMP signaling is associated with the formation of tumors (292–295, 393, 394); in these tissues, enhancement of PDE function is potentially desirable. Currently, there are no drugs that induce PDE activation.
V. Conclusions and Perspectives
By hydrolyzing cAMP and/or cGMP, PDEs play a critical role in regulation of cellular functions. Their subcellular localization, structural diversity, and unique regulation allow each PDE variant to regulate compartmentalized cyclic nucleotide signaling pathways and to define specific cell responses in an integrated manner. The intracellular signaling pathways controlled by PDEs can be altered in many pathological conditions, including cancer, inflammatory diseases, neurodegenerative and endocrine disorders, and reciprocally, various pathologies are able to selectively alter PDE regulation, providing a rationale for the use of PDE inhibitors in the treatment of different diseases. After having addressed the delivery, stability, and toxicity issues related to these peptide drugs, pathologies in which variant PDE activity is increased or decreased might potentially be cured with molecules that affect PDE function.
Acknowledgments
This work was supported by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH), protocol HD008920; and in part by the intramural program of the National Heart, Lung, and Blood Institute, NIH; the Department of Pediatrics, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; the Endocrinology Unit, Faculty of Medicine, University of Brasilia, Brasilia, Brazil; Graduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Brazil; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil; and Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- AhR
- aryl hydrocarbon receptor
- AKAP
- A-kinase-anchoring protein
- β-AR
- β-adrenergic receptor
- CaM
- calmodulin
- COPD
- chronic obstructive pulmonary disease
- CNGC
- cyclic nucleotide-gated channel
- CREB
- cAMP response element-binding protein
- EPAC
- exchange protein activated by cAMP
- FRET
- fluorescence resonance energy transfer
- GAF
- cGMP-specific PDEs, adenylyl cyclases and FhIA
- GPCR
- G protein-coupled receptor
- IBMX
- 1-methyl-3-isobutylxanthine
- LTCC
- L-type Ca2+ channel
- mAKAP
- muscle-specific AKAP
- MDD
- major depressive disorder
- MPF
- maturation-promoting factor
- NO
- nitric oxide
- NOS
- NO synthase
- PAS
- per-arnt-sim
- PCOS
- polycystic ovary syndrome
- PDE
- phosphodiesterase
- PI3K
- phosphatidylinositol-3 kinase
- PKA
- protein kinase A
- PKB
- protein kinase B
- PKG
- cGMP-dependent protein kinase
- PLB
- phospholamban
- PP
- protein phosphatase
- REC
- cheY-homologous receiver domain
- RyR
- ryanodine receptor
- SERCA2
- SR Ca2+ ATPase
- sGC
- soluble guanylyl cyclase
- SR
- sarcoplasmic reticulum
- UCR
- upstream conserved region.
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