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Phosphodiesterase 11: A brief review of structure, expression and function
Abstract
Phosphodiesterase 11 (PDE11) is the latest isoform of the phosphodiesterase family to be identified. Interest in PDE11 has increased recently because tadalafil, an oral phosphodiesterase 5 inhibitor, cross reacts with PDE11. The function of PDE11 remains largely unknown, but growing evidence points to a possible role in male reproduction. The published literature on PDE11 structure, function and expression is reviewed.
... of the GAF-B domain within its N-terminal region [14] (Fig. 1). The unique nature of the N-terminal regulatory region of each PDE11A isozyme [9,14,38] may provide novel inroads for selectively targeting a single PDE11A isozyme with high selectivity. ...
... Finally, phosphorylation and other predicted post-translational modifications (Fig. 3) may offer yet another mechanism to regulate catalytic activity and subcellular localization of PDE11A. The fact that the N-terminal regulatory region of each PDE11A isozyme is unique [9,14,38] may provide a mechanism to selectively target the function of a single PDE11A isozyme with high selectivity. Indeed, isozyme-specific targeting of PDE11A activity has already been demonstrated as vinpocetine can inhibit PDE11A3 but not PDE11A4 [11]. ...
... The catalytic site of PDE11A hydrolyzes both cAMP and cGMP under physiological conditions (cf. [38]). Though the catalytic properties vary between isoforms, each of the PDE11A variants break down cAMP and cGMP with similar affinities and maximal catalytic rates [9][10][11][12][13] [10]. ...
Phosphodiesterase 11A (PDE11A) is the most recently discovered 3',5'-cyclic nucleotide phosphodiesterase. By breaking down both cAMP and cGMP, PDE11A is a critical regulator of intracellular signaling. To date, PDE11A has been implicated to play a role in tumorigenesis, brain function, and inflammation. Here, we consolidate and, where necessary, reconcile the PDE11A literature to evaluate this enzyme as a potential therapeutic target. We compare the results and methodologies of numerous studies that report conflicting tissue expression profiles for PDE11A. We conclude that PDE11A expression is relatively restricted in the body, with reliable expression reported in tissues such as the brain (particularly the hippocampus), the prostate, and the adrenal gland. Each of the four PDE11A splice variants (PDE11A1-4) appears to exhibit a distinct tissue expression profile and has a unique N-terminal regulatory region, suggesting that each isoform could be individually targeted with a small molecule or biologic. Progress has been made in identifying a tool PDE11A inhibitor as well as an activator; however, the functional effects of these pharmacological tools remain to be determined. Importantly, PDE11A knockout mice do exist and appear healthy into late age, suggesting a potential safety window for targeting this enzyme. Considering the implication of PDE11A in disease-relevant biology, the potential to selectively target specific PDE11A variants, and the possibility of either activating or inhibiting the enzyme, we believe PDE11A holds promise as a potential future therapeutic target.
... PDE11 is the most recently identified PDE and exhibits a dual substrate specificity for both cAMP and cGMP [134]. It is encoded by only one gene, PDE11A, that produces four variants (PDE11A1-PDE11A4) displaying different amino termini [135] (Figure 11). fertilize oocytes [133]. ...
... PDE11 is the most recently identified PDE and exhibits a dual substrate specificity for both cAMP and cGMP [134]. It is encoded by only one gene, PDE11A, that produces four variants (PDE11A1-PDE11A4) displaying different amino termini [135] (Figure 11). In humans, PDE11A is relatively highly expressed in skeletal muscle and prostate while moderate expression levels have been detected in the testis, pituitary and thyroid glands [137]. ...
Phosphodiesterases are key regulators that fine tune the intracellular levels of cyclic nucleotides, given their ability to hydrolyze cAMP and cGMP. They are critical regulators of cAMP/cGMP-mediated signaling pathways, modulating their downstream biological effects such as gene expression, cell proliferation, cell-cycle regulation but also inflammation and metabolic function. Recently, mutations in PDE genes have been identified and linked to human genetic diseases and PDEs have been demonstrated to play a potential role in predisposition to several tumors, especially in cAMP-sensitive tissues. This review summarizes the current knowledge and most relevant findings regarding the expression and regulation of PDE families in the testis focusing on PDEs role in testicular cancer development.
... Moreover, PDE11 selectivity of udenafil (selectivity ratio: 96) is higher than that of tadalafil (selectivity ratio: 7.1) [13]. Although its function is not yet clear, PDE11 is widely distributed in the skeletal muscle, testes, heart, prostate, kidney, liver, and pituitary [14]. Therefore, udenafil was found to be safe and well tolerated in human subjects. ...
Purpose:
To evaluate the efficacy and safety of udenafil 75 mg once daily in patients with erectile dysfunction following bilateral nerve-sparing robot-assisted laparoscopic radical prostatectomy (BNS-RALP).
Materials and methods:
A multi-center, prospective, randomized, controlled, double-blind study was conducted. Among patients with localized prostate cancer with international index of erectile function-erectile function domain (IIEF-EF) score of 18 or higher before BNS-RALP, those who developed postoperative erectile dysfunction (IIEF-EF score 14 or less at 4 weeks after BNS-RALP) were enrolled. Enrolled patients were randomly assigned to the udenafil 75 mg daily group or the placebo group in a 2:1 ratio. Each subject was followed up at 8 weeks (V2), 20 weeks (V3), and 32 weeks (V4) to evaluate the efficacy and safety of udenafil.
Results:
In all, 101 patients were screened, of whom 99 were enrolled. Of the 99 patients, 67 were assigned to the experimental group and 32 to the control group. Ten (14.93%) patients in the experimental group and 10 (31.25%) in the control group dropped out of the study. After 32 weeks of treatment, IIEF-EF score of 22 or higher was seen in 36.51% (23/63) of patients in the experimental group and 13.04% (3/23) patients in the control group (p=0.021). The proportion of patients with IIEF-EF improvement of 25% or more compared to the baseline was 82.54% (52/63) in the experimental group and 62.96% (17/27) in the control group (p=0.058).
Conclusions:
Udenafil 75 mg once daily after BNS-RALP improved the erectile function without any severe adverse effects.
... Besides, it should also be noted that members of the PDE protein superfamily, that is, phosphodiesterase 11A (PDE11A), play important roles in the control of cyclic nucleotide signaling [56]. Other studies reported that the expression of this gene was prominent in the prostate and testes [57,58]. Another study founded that strong immune signals were obtained for PDE11A in the acrosomal cap and flagella of spermatozoa [59]. ...
Background
Tobacco smoking is considered as one of the lifestyles factors that influence the sperm DNA methylation and global sperm DNA methylation and that may affect the sperm phenotype. This study was performed to investigate whether tobacco cigarette heavy smoking influences sperm DNA methylation patterns and semen parameters and to determine whether there is an alteration in the transcription level of MAPK8IP3 , GAA , ANXA2 , PRRC2A , and PDE11A genes in heavy smokers compared to non-smokers. Thirty samples were subjected to 450K arrays as a screening study to assess the variation in sperm DNA methylation levels between heavy smokers and non-smokers. Five CpG sites have the highest difference in methylation levels (cg07869343, cg05813498, cg09785377, cg06833981, and cg02745784), which are located in the MAPK8IP3 , GAA , ANXA2 , PRRC2A , and PDE11A genes, respectively, and were selected for further analysis using deep bisulfite sequencing in 280 independent samples (120 proven non-smokers and 160 heavy smokers) with a mean age of 33.8 ± 8.4 years. The global sperm DNA methylation, sperm DNA fragmentation, and chromatin non-condensation were evaluated also.
Results
A significant increase was found in the methylation level at seven, three, and seventeen CpGs within the GAA , ANXA2 , and MAPK8IP3 genes amplicon, respectively ( P < 0.01) in heavy smokers compared to non-smokers. Additionally, a significant increase was found in the methylation levels at all CpGs within PRRC2A and PDE11A gene amplicon ( P < 0.01). A significant increase was found in the level of sperm chromatin non-condensation, DNA fragmentation, and global DNA methylation ( P < 0.001) in heavy smokers compared to non-smokers.
Conclusion
These results indicate that tobacco cigarette smoking can alter the DNA methylation level at several CpGs, the status of global DNA methylation, and transcription level of the following genes “ MAPK8IP3 , GAA, ANXA2, PRRC2A , and PDE11A ” in human spermatozoa. These findings may affect negatively semen parameters and men’s fertility.
... Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase-11 binds both cAMP and cGMP and bears similarity to PDE-5. 45,46 Phosphatidylethanolamine-binding protein 1 acts as a tumor suppressor gene and also activates the beta-adrenergic receptor, playing an adaptive role in heart failure. [47][48][49] From the cardiovascular risk standpoint, among these 8 proteins, platelet-activating factor acetylhydrolase IB subunit beta (lipoproteinassociated phospholipase A2) has been suspected of being involved in the pathogenesis of atherosclerosis. ...
Background
Chronic kidney disease ( CKD ) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers ( SOMA scan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD .
Methods and Results
Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman‐rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P <0.05 (ρ 0.06–0.74); 218 (20.7%) proteins correlated with eGFR moderately or strongly (ρ 0.2–0.74). Among the previously identified 196 protein cardiovascular biomarkers, just 87 remained prognostic after correction for eGFR . Among patients with CKD ( eGFR <60 mL/min per 1.73 m ² ), we identified 21 protein cardiovascular risk biomarkers of which 8 are unique to CKD.
Conclusions
CKD broadly alters the composition of the circulating proteome. We describe protein biomarkers capable of predicting cardiovascular risk independently of glomerular filtration, and those that are prognostic of cardiovascular risk specifically in patients with CKD and even unique to patients with CKD .
... Several literatures indicate that PDEs preferentially hydrolyse adenosine triphosphate, but can also work on other nucleoside 5 0 triphosphates such as guanosine triphosphate, cytidine triphosphate, thymidine triphosphate, and cyclic adenosine monophosphate, etc., involving in diverse regulation. Indeed, all PDEs share a highly conserved catalytic domain near the carboxy-terminus with minor variations that are considered to be responsible for their selectivity, whilst Nterminus part contains more substantial variations (Makhlouf et al., 2006). In any case, for the first time, an extracellular carbaryl hydrolase was purified and annotated as PDEs, although its comprehensive characteristics, including optimum catalytic conditions, kinetic assays and substrate specificity, are needed to be explored. ...
Pesticides introduced inadvertently or deliberately into environment by anthropogenic activity have caused growing global public concern, therefore the search of approaches for elimination of such xenobiotics should be encouraged. A cypermethrin-degrading bacterial strain Bacillus licheniformis B-1 was found to efficiently degrade carbaryl in LB medium at concentrations of 50–300 mg L−1 within 48 h, during which temperature and pH played important roles as reflected by increase in pollutant depletion. A stimulatory effect of Fe3+ and Mn2+ on microbial growth was observed, whereas Cu2+ caused inhibition of degradation. Results showed that 1-naphthol was a major transformation product of carbaryl which was further metabolised. An approximately 29 kDa carbaryl-degrading enzyme was purified from B-1 with 15.93-fold purification and an overall yield of 6.02% was achieved using ammonium sulphate precipitation, DEAE-Sepharose CL-6B anion-exchange chromatography and Sephadex G-100 gel filtration. The enzyme was identified through nano reversed-phase liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry as a phosphodiesterase (PDE). This is the first report on the characterization of carbaryl-degrading by Bacillus spp. and the role of a PDE in carbaryl-detoxifying. Also, strain B-1 showed versatile in carbosulfan, isoprocarb and chlorpyrifos degradation, demonstrating as ideal candidate for environment bioremediation
... Phosphodiesterase inhibitors (PDEs) increase intracellular cyclic adenosine monophosphate, which results in a wide range of anti-inflammatory effects and pathologically leads to improve asthma and chronic obstructive pulmonary disease. [1][2][3] Increasing intracellular cyclic adenosine monophosphate concentration contributes to decrease and inhibit the release of inflammatory mediators from mastocytes and eosinophils. It also results in the cessation of inflammatory cytokines products, such as TNF-alpha, IL-2, IFN-α, and IL-4. ...
Introduction:
Phosphodiesterase inhibitors (PDEs) increase intracellular cyclic adenosine monophosphate, which results in a wide range of anti-inflammatory effects and pathologically leads to improve asthma disease. Because no human study has surveyed the effect of PDEs on pulmonary function, except some case reports and animal researches, we decided to perform a pilot study for evaluating the effect of sildenafil (PDE5) on pulmonary function in patients with severe asthma.
Methods:
This randomized controlled trials study was conducted on 20 patients with severe asthma in 2019 in Iran. For case group, was prescribed sildenafil (50 mg) daily and the control group received the placebo. In the beginning of the study and one month later, volume parameters, 6-minute walk distance (6MWD), and the quality-of-life questionnaire were measured and compared in the two groups.
Results:
Twenty patients were entered into this study. 8 patients (40%) were male and 12 (60%) were female. The results showed that mean forced vital capacity 1 in the sildenafil group turned from 1259 ± 170 to 1603 ± 527, while in the placebo group it changed from 1135 ± 125 to 1365 ± 251 (P-value = 0.215). There is no statistically significant difference between two groups. In addition, in comparison with placebo, sildenafil did not show any significant improvement in the volume parameters, the quality-of-life questionnaire scale, and 6MWD at the end of the study.
Conclusion:
According to present result can be concluded that sildenafil does not improve the severity of asthma and the quality of life in patients with severe asthma.
... Tadalafil inhibits both PDE5 and PDE11 enzymes; PDE11 enzyme is abundant in skeletal muscle. Inhibition of PDE11 with tadalafil leads to the common side effects, namely, back and muscle pain (myalgia) (Makhlouf, Kshirsagar, & Niederberger, 2006). It was found that the catalytic site of PDE11 resembles that of PDE5, however, there is no available crystal structure for PDE11 and no adequate knowledge about its physiological role in human body. ...
Hit, Lead & Candidate Discovery
Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)‐6‐(1,3‐benzodioxol‐5‐yl)‐2‐methyl‐2,3,6,7,12,12a‐hexahydropyrazino[1′,2′:1,6] pyrido[3,4‐b]indole‐1,4‐dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis‐(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC50 = 5 nM. It possesses high selectivity for PDE5 versus PDE1‐4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.
... Çünkü PDE11'in insanlardaki etki mekanizması tam olarak açıklığa kavuşturulmuş değildir. [20] Aksesuar gland enfeksiyonu olan erkeklerin seminal vezi- küllerinin karakteristik ultrason görüntüleri mevcuttur. [21] Bu vezikülit tipleri ultrasonda, "hipertorfik-konjestif" veya "fibro-sklerotik" şekilde görülebilir. ...
... PDE11A is inhibited by dipyridamole (IC 50 = 0.9-1.8 mM), zaprinast (IC 50 = 5-33 mM), IBMX (IC 50 = 25-81 mM), and is insensitive to EHNA, rolipram, and milrinone. There is no selective inhibitor for PDE11A; however, amongst the newly launched PDE5 inhibitors, tadalafil was the most potent (IC 50 = 37-73 nM), inhibiting both cAMP and cGMP hydrolysis [200,201]. ...
Phosphodiesterases are a group of enzymes that hydrolyze cyclic nucleotides, which assume a key role in directing intracellular levels of the second messengers' cAMP and cGMP, and consequently cell function. The disclosure of 11 isoenzyme families and our expanded knowledge of their functions at the cell and molecular level stimulate the improvement of isoenzyme selective inhibitors for the treatment of various diseases, particularly cardiovascular diseases. Hence, future and new mechanistic investigations and carefully designed clinical trials could help reap additional benefits of natural/synthetic PDE inhibitors for cardiovascular disease in patients. This review has concentrated on the potential therapeutic benefits of phosphodiesterase inhibitors on cardiovascular diseases.
... should also be noted that members of the PDE protein superfamily, that is, phosphodiesterase 11A (PDE11A), play important roles in the control of cyclic nucleotide signalling (Jäger et al., 2012). Other studies by Fawcett et al. (2000), Yuasa, Ohgaru, Asahina, and Omori (2001), Loughney, Taylor, and Florio (2005) and Makhlouf, Kshirsagar, and Niederberger (2006) reported that the expression of this gene was prominent in prostate and testes. Baxendale and Fraser (2005) founded that strong immunosignals T A B L E 6 (Continued) (Continues) were obtained for PDE11A in the acrosomal cap and flagellum of spermatozoa. ...
The purpose of this study was to assess the relationship between alterations in sperm DNA methylation levels and sperm count and sperm motility. Five CpG sites underwent deep bisulphite sequencing to validate the observed methylation difference in 78 samples (28 proven fertile males "controls," and 50 subfertile males "cases"). The results showed that variation in methylation levels was found in more than one CpG: the DNA methylation levels in CpG1, CpG2 and CpG3 of the PRRC2A gene-related amplicon showed high significant differences in the case group compared to the control group (p ≤ .0001, p ≤ .003, and p ≤ .0001 respectively). Moreover, three CpGs of the four CpGs tested within the ANXA2 gene-related amplicon (CpG1, CpG3 and CpG4) were significantly different (p ≤ .002, p ≤ .001, and p ≤ .0001, respectively) in the case group compared to the control group. In addition, a significant difference was found in seven CpGs of the twenty-two CpGs tested within the MAPK8Ip3 gene-related amplicon, besides six CpGs of the ten CpGs tested within the GAA gene-related amplicon between case and control groups. In conclusion, this study identifies that CpGs have a significantly different in methylation levels of sperm DNA for subfertile males.
... Inhibition of this enzyme, seen principally with sildenafil and vardenafil causes disturbances in color perception [26]. Tadalafil, on the other hand, cross-reacts with PDE11, an enzyme expressed in the heart, liver, pituitary, and prostate with physiological functions that are still not clarified [47]. A comparison of pharmacologic properties and side effect profile between the different PDE5 inhibitors is depicted in Table 13.4. ...
Erectile dysfunction (ED) is defined as the persistent inability to attain or maintain penile erection sufficient for satisfactory sexual performance. Despite its benign nature, ED may affect the physical and psychosocial well-being of sufferers, causing a significant impact on their quality of life (QoL). Recent evidence has pondered ED as an early manifestation of cardiovascular disease suggesting that its occurrence should not be dealt with as only a QoL issue, but also as a potential warning sign of a more serious medical condition. With an increasing knowledge about possible disturbances of penile erection, new organically oriented therapeutic options have been developed, which have revolutionized the treatment of ED. Through the use of clinical scenarios, this chapter reviews the available approaches for the evaluation and management of patients presenting with ED.
... Apart from this reasonable basis for the foundation of vision-related side effects by consequence of direct inhibition of PDE6 which is in line with the location/function of PDE6; another hypothesis ascribed these side effects to the reactivity of these drugs targeting to PDE5 isoenzymes that are distributed in tissues other than the corpus cavernosum 36,37 . In addition, tadalafil is a dual inhibitor of PDE5 and PDE11 enzymes which is thought to be the reason of back and muscle pain (myalgia) during the treatment of men with tadalafil since PDE11 enzymes are abundantly found in skeletal muscle cells 38,39 . Although the catalytic site of PDE11 is the most similar one with PDE5, the absence of crystal structure together with the inadequate knowledge about the physiological role of this enzyme in human body restrict the understanding of the mechanism of the inhibitory activity of this target. ...
The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3′,5′-cyclic guanosine monophosphate (cGMP) and/or 3′,5′-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the “clean drug-like subset of ZINC database” that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.
... Here we aim to review current knowledge on cAMP-specific phosphodiesterases and will describe their properties, distribution, and regulation and what is currently known about their inhibition by conventional-active-site directed compounds, novel allosteric inhibitor classes, and novel peptide disruptors. We will not discuss either cGMP-specific phosphodiesterases or dual cAMP-cGMP phosphodiesterses, as many more recent reviews have appraised current developments in those areas [10][11][12][13][14][15][16]. ...
... The highest expression levels of PDE9A are in the brain, spleen, small intestine and kidneys (Fisher et al., 1998;Rentero et al., 2003). In the brain, PDE9A is the Makhlouf et al. (2006) most highly expressed PDE (Andreeva et al., 2001) and almost all cell signaling pathways pass through cGMP. Regulation of the synthesis and degradation of cGMP fluctuates in different regions of the brain depending on physiological and pathological states. ...
This review focuses on the development of drugs targeting phosphodiesterase 9A (PDE9A). PDE9A normally regulates cGMP (cyclic guanosine monophosphate) levels, which in turn regulate signal transduction. However, in pathological conditions, PDE9A inhibition is required to treat diseases that lower the level of cGMP. Hence, there is a need for specific PDE9A inhibitors. Aligning the 3D structure of PDE9A with other phosphodiesterases reveals residues crucial to inhibitor selectivity. GLU406 is unique to PDE9A and stabilizes the side chain of an invariant glutamine (GLN453). TYR424 is another relevant residue, unique only to PDE9A and PDE8A. Therefore, TYR424 could discriminate between PDE9A and all other PDEs except PDE8A. TYR424 should also be considered in the design of selective inhibitors because PDE8A has low expression levels in the brain. Hence, GLU406 and TYR424 are important target residues in the design of PDE9A-selective inhibitors.
... In addition, reporting of mild vasodilatory effects like headache, flushing, dyspepsia and nasal congestion or rhinitis is commonly recorded for all PDE5 inhibitors (Markou et al., 2004;Seftel, 2004;Kim et al., 2008;Tsertsvadze et al., 2009). However, abnormalities of vision or myalgias that are often experienced by patients receiving tadalafil or sildenafil (Makhlouf et al., 2006) were not reported in this study, confirming udenafil's high selectivity for PDE5. ...
... To date, 11 families and several isoforms of PDEs have been identified based on their amino acid sequence, biochemical, and inhibitors profiles. Different PDEs can share the same catalytic function, but may differ in tissue expression and intracellular localization [2]. Elevation of cAMP induces cAMP-dependent protein kinase A (PKA) activation. ...
Cyclic nucleotides cAMP and cGMP are part of almost all major cellular signaling pathways. Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cAMP and cGMP. Protein kinase A or cAMP-dependent protein kinase mediates most cAMP effects in the cell. Over the last 25 years, various components of this group of molecules have been involved in human diseases, both genetic and acquired. Lately, the PDEs attract more attention. The pharmacological exploitation of the PDE's ability to regulate cGMP and cAMP, and through them, a variety of signaling pathways, has led to a number of new drugs for diverse applications from the treatment of erectile dysfunction to heart failure, asthma, and chronic obstructive pulmonary disease. We present the abstracts (available online) and selected articles from the proceedings of a meeting that took place at the National Institutes of Health (NIH), Bethesda, MD, June 8-10, 2011.
... To date, 11 PDE gene families have been identified, based on their amino acid sequences, biochemical properties, and inhibitor profiles. Different PDEs can share the same catalytic function, but may differ in tissue expression and intracellular localization (Table 1) [2]. ...
Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implicated in predisposition to tumor formation. This review focuses on the possible function of PDEs in a variety of tumors, primarily in endocrine glands, both in tumor predisposition and as potential therapeutic targets.
... In human adipose tissue, phosphodiesterase type 3B (PDE3B) is known to be widely expressed [12]. PDE5 has also been detected recently in human adipocytes, and its expression levels are modulated during adipose differentiation in vitro [12,13], together with phosphodiesterase type 11 (PDE11) [13], which shows high sequence homology to PDE5 [14] and acts on both cAMP and cGMP with similar K m values [6]. Interestingly, recent reports show that PDE5 inhibition with subsequent PKG activation increases differentiation of 3T3-L1 preadipocytes and aromatase activity in human adipocytes [13,15]. ...
Phosphodiesterase type 5 (PDE5) is expressed in many tissues (e.g. heart, lung, pancreas, penis) and plays a specific role in hydrolyzing cyclic guanosine monophosphate (cGMP). In adipocytes, cGMP regulates crucial functions by activating cGMP-dependent protein kinase (PKG). Interestingly, PDE5 was recently identified in adipose tissue, although its role remains unclear. Its inhibition, however, was recently shown to affect adipose differentiation and aromatase function. This review summarizes evidence supporting a role for the PDE5-regulated cGMP/PKG system in adipose tissue and its effects on adipocyte function. A better elucidation of the role of PDE5 in the adipocyte could reveal new therapeutic strategies for fighting obesity and metabolic syndrome.
... The most recently discovered of the PDE families is PDE11A, which catalyzes the hydrolysis of cAMP and cGMP equally well (Francis 2005;Yuasa et al. 2001;Weeks et al. 2007). The first report of PDE11A was by Fawcett et al. (2000), who identified a partial sequence from a commercially available expressed sequence tag database based on homology with other mammalian PDEs (Makhlouf et al. 2006). Four splicing variants of PDE11A have been discovered, PDE11A1-4. ...
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that are involved in the regulation of the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) by controlling their rates of hydrolysis. There are 11 different PDE families and each family typically has multiple isoforms and splice variants. The PDEs differ in their structures, distribution, modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown to play distinct roles in processes of emotion and related learning and memory processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or cGMP, modulate mood and related cognitive activity. This review discusses the current state and future development in the burgeoning field of PDEs in the central nervous system. It is becoming increasingly clear that PDE inhibitors have therapeutic potential for the treatment of neuropsychiatric disorders involving disturbances of mood, emotion, and cognition.
... In addition, with regard to PDE11, udenafil (selectivity ratio: 96) displayed much higher selectivity than tadalafil (selectivity ratio: 7.1) [25]. Although its function is not yet clear, PDE11 is widely distributed in skeletal muscle, testes, heart, prostate, kidney, liver, and pituitary [26]. Therefore, udenafil was found to be safe and well tolerated in human subjects. ...
A once-daily dosing regimen with a phosphodiesterase type 5 inhibitor is needed for the treatment of erectile dysfunction (ED), in part because of the behavioral complexities associated with sexual intimacy. Many patients prefer spontaneous rather than scheduled sexual activities or they anticipate frequent sexual encounters. The pharmacokinetic profiles of udenafil with a time of maximal concentration of 1.0-1.5h and a terminal half-life of 11-13 h make udenafil a good candidate for once-daily dosing.
To evaluate the efficacy and safety of once-daily dosing of udenafil in the treatment of ED.
This multicenter randomized double-blind, placebo-controlled, fix-dosed clinical trial involved 237 patients with ED. The subjects, who were treated with placebo or udenafil (25mg, 50mg, or 75 mg) once daily for 12 wk, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ) during the study.
The primary outcome parameter was the change from baseline for the IIEF erectile function domain (EFD) score. The secondary outcome parameters were SEP questions 2 and 3, the shift to normal rate (EFD ≥ 26), and the response to the GAQ.
Compared with placebo, patients who took 50mg or 75 mg of udenafil had a significantly improved IIEF-EFD score. Similar results were observed in comparing questions 2 and 3 in the SEP diary and the GAQ. Flushing was the most common treatment-related adverse event, which was transient and mild to moderate in severity.
Udenafil significantly improved erectile function among ED patients when administered in doses of 50mg or 75 mg once daily for 12 wk. Daily administration of udenafil (50mg) may be another treatment option for ED.
... There is evidence for PDE11 expression in skeletal muscle, prostate, testis and salivary glands. The function of PDE11 remains largely unknown, but growing evidence points to a possible role in male reproduction [49]. ...
Phosphodiesterase inhibitors (PDEIs) are a class of drugs that are widely used because of their various pharmacological properties including cardiotonic, vasodilator, smooth muscle relaxant, antidepressant, antithrombotic, bronchodilator, antiinflammatory and enhancer of cognitive function. In the recent years, interest in drugs of plant origin has been progressively increased. Some pharmacologically active substances that come from plants demonstrate PDEI activity. They mainly belong to alkaloids, flavonoids, and saponins. In this review, studies on herbal PDEI were reviewed and their possible therapeutic applications were discussed. Screening plants for PDE inhibitory activity may help to develop standardized phytotherapeutic products or find new sources for new lead structures with PDEI pharmacological activity. The studies discussed in this paper are mainly in vitro and for more reasonable and conclusive results, it is required to conduct in vivo and finally human and clinical tests.
Oxygen sensing is of paramount importance for maintaining cellular and systemic homeostasis. In response to diminished oxygen levels, the hypoxia-inducible factors (HIFs) orchestrate various biological processes. These pivotal transcription factors have been identified as key regulators of several biological events. Notably, extensive research from our group and others has demonstrated that HIF1α exerts an inverse regulatory effect on steroidogenesis, leading to the suppression of crucial steroidogenic enzyme expression and a subsequent decrease in steroid levels. These steroid hormones occupy pivotal roles in governing a myriad of physiological processes. Substantial or prolonged fluctuations in steroid levels carry detrimental consequences across multiple organ systems and underlie various pathological conditions, including metabolic and immune disorders. MicroRNAs serve as potent mediators of multifaceted gene regulatory mechanisms, acting as influential epigenetic regulators that modulate a broad spectrum of gene expressions. Concomitantly, phosphodiesterases (PDEs) play a crucial role in governing signal transduction. PDEs meticulously manage intracellular levels of both cAMP and cGMP, along with their respective signaling pathways and downstream targets. Intriguingly, an intricate interplay seems to exist between hypoxia signaling, microRNAs, and PDEs in the regulation of steroidogenesis. This review highlights recent advances in our understanding of the role of microRNAs during hypoxia-driven processes, including steroidogenesis, as well as the possibilities that exist in the application of HIF prolyl hydroxylase (PHD) inhibitors for the modulation of steroidogenesis.
Capillary leak syndrome (CLS) represents a phenotype of increased fluid extravasation, resulting in intravascular hypovolemia, extravascular edema formation and ultimately hypoperfusion. While endothelial permeability is an evolutionary preserved physiological process needed to sustain life, excessive fluid leak—often caused by systemic inflammation—can have detrimental effects on patients’ outcomes. This article delves into the current understanding of CLS pathophysiology, diagnosis and potential treatments. Systemic inflammation leading to a compromise of endothelial cell interactions through various signaling cues (e.g., the angiopoietin–Tie2 pathway), and shedding of the glycocalyx collectively contribute to the manifestation of CLS. Capillary permeability subsequently leads to the seepage of protein-rich fluid into the interstitial space. Recent insights into the importance of the sub-glycocalyx space and preserving lymphatic flow are highlighted for an in-depth understanding. While no established diagnostic criteria exist and CLS is frequently diagnosed by clinical characteristics only, we highlight more objective serological and (non)-invasive measurements that hint towards a CLS phenotype. While currently available treatment options are limited, we further review understanding of fluid resuscitation and experimental approaches to target endothelial permeability. Despite the improved understanding of CLS pathophysiology, efforts are needed to develop uniform diagnostic criteria, associate clinical consequences to these criteria, and delineate treatment options.
Graphical Abstract
Xanthine is a versatile nitrogenous alkaloid. The pharmaceutical active nature of xanthine derivatives is widely known for treating various diseases. Therefore, xanthine can act as structurally rigid scaffold which provides enormous possibility for molecular diversity in drug development process. Xanthine based compounds are reported for their non-specific phosphodiesterase inhibition, however, xanthine based inhibitors have not been reported for PDE9A inhibition. With introduction of “xanthine” as a scaffold, the present study was an attempt to bring molecular diversification in PDE9A research. The current study was emphasized on two approaches – one was virtual screening to find out the possibilities of existing xanthine based derivatives to regulate the catalytic action of PDE9A and the second approach was to use the xanthine as scaffold for designing new xanthine derivatives and again the same xanthine was used as ‘starting material’ for synthesizing selected xanthine derivatives. Two schemes were developed based on getting clear understanding over the molecular structure of xanthine. The biological studies were carried out to understand the biological affinity of the selected virtual screened compounds and chemically synthesized new compounds by using spectrophotometric inhibition studies for structural activity relationship (SAR) analysis and thermal shift assay for stability studies of protein-ligand complex. The biological studies showed chemically synthesized xanthine derivatives as better inhibitors than virtual screened compounds.
cAMP and cGMP are important secondary messengers involved in cell regulation and metabolism driven by the G protein‑coupled receptor. cAMP is converted via adenylyl cyclase (AC) and activates protein kinase A to phosphorylate intracellular proteins that mediate specific responses. cAMP signaling serves a role at multiple steps in tumorigenesis. The level of cAMP is increased in association with cancer cell formation through activation of AC‑stimulatory G protein by mutation. Phosphodiesterases (PDEs) hydrolyze cAMP and cGMP to AMP and GMP. PDEs are composed of 11 families, and each can hydrolyze cAMP and cGMP or both cAMP and cGMP. PDEs perform various roles depending on their location and expression site, and are involved in several diseases, including male erectile dysfunction, pulmonary hypertension, Alzheimer's disease and schizophrenia. PDE11A is the 11th member of the PDE family and is characterized by four splice variants with varying tissue expression and N‑terminal regulatory regions. Among tissues, the expression of PDE11A was highest in the prostate, and it was also expressed in hepatic skeletal muscle, pituitary, pancreas and kidney. PDE11A is the first PDE associated with an adrenocortical tumor associated genetic condition. In several studies, three PDE11A mutations have been reported in patients with Cushing syndrome with primary pigmented nodular adrenocortical disease or isolated micronodular adrenocortical disease without other genetic defects. It has been reported that an increase in PDE11A expression affects the proliferation of glioblastoma and worsens patient prognosis. The present mini‑review summarizes the location of PDE11A expression, the impact of structural differences and disease relevance.
Aims
Ischemia/reperfusion (I/R) occurs in renal artery stenosis, partial nephrectomy and most commonly during kidney transplantation. It brings serious consequences such as DGF (Delayed Graft Function) or organ dysfunction leading to renal failure and ultimate death. There is no effective therapy to handle the consequences of Renal Ischemia/Reperfusion (I/R) injury. Cyclic nucleotides, cAMP and cGMP are the important second messengers that stimulate intracellular signal transduction for cell survival in response to growth factors and peptide hormones in normal tissues and in kidneys plays significant role that involves vascular tone regulation, inflammation and proliferation of parenchymal cells. Renal ischemia and subsequent reperfusion injury stimulate signal transduction pathways involved in oxidative stress, inflammation, alteration in renal blood flow leading to necrosis and apoptosis of renal cell.
Materials and methods
An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out. To understand the functioning of Phosphodiesterases (PDEs) and its pharmacological modulation in Renal Ischemia-Reperfusion Injury.
Key findings
Current therapeutic options may not be enough to treat renal I/R injury in group of patients and therefore, the current review has discussed the general characteristics and physiology of PDEs and preclinical-studies defining the relationship between PDEs expression in renal injury due to I/R and its outcome on renal function.
Significance
The role of PDE inhibitors in renal I/R injury and the clinical status of drugs for various renal diseases have been summarized in this review.
Accounts in Drug Discovery describes recent case studies in medicinal chemistry with a particular emphasis on how the inevitable problems that arise during any project can be surmounted or overcome. The Editors cover a wide range of therapeutic areas and medicinal chemistry strategies, including lead optimization starting from high throughput screening "hits" as well as rational, structure-based design. The chapters include "follow-ons" and "next generation" compounds that aim to improve upon first generation agents. This volume surveys the range of challenges commonly faced by medicinal chemistry researchers, including the optimization of metabolism and pharmacokinetics, toxicology, pharmaceutics and pharmacology, including proof of concept in the clinic for novel biological targets. The case studies include medicinal chemistry stories on recently approved and marketed drugs, but also chronicle "near-misses", i.e., exemplary compounds that may have proceeded well into the clinic but for various reasons did not result in a successful registration. As the vast majority of projects fail prior to registration, much can be learned from such narratives. By sharing a wide range of drug discovery experiences and information across the community of medicinal chemists in both industry and academia, we believe that these accounts will provide insights into the art of medicinal chemistry as it is currently practiced and will help to serve the needs of active medicinal chemists.
Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides and maintain physiologic levels of intracellular concentrations of cyclic adenosine and guanosine mono-phosphate (cAMP and cGMP, respectively). Increased cAMP signaling has been associated with adrenocortical tumors and Cushing syndrome. Genetic defects in phosphodiesterase 11A (PDE11A) may lead to increased cAMP signaling and have been found to predispose to the development of adrenocortical, prostate, and testicular tumors. A previously reported Pde11a knockout (Pde11a-/-) mouse line was studied and found to express PDE11A mRNA and protein still, albeit at reduced levels; functional studies in various tissues showed increased cAMP levels and reduced PDE11A activity. Since patients with PDE11A defects and Cushing syndrome have PDE11A haploinsufficiency, it was particularly pertinent to study this hypomorphic mouse line. Indeed, Pde11a-/- mice failed to suppress corticosterone secretion in response to low dose dexamethasone, and in addition exhibited adrenal subcapsular hyperplasia with predominant fetal-like features in the inner adrenal cortex, mimicking other mouse models of increased cAMP signaling in the adrenal cortex. We conclude that a previously reported Pde11a-/- mouse showed continuing expression and function of PDE11A in most tissues. Nevertheless, Pde11a partial inactivation in mice led to an adrenocortical phenotype that was consistent with what we see in patients with PDE11A haploinsufficiency.
The second messenger molecule 3′5′-cyclic adenosine monophosphate (cAMP) imparts several beneficial effects in lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). While cAMP is bronchodilatory in asthma and COPD, it also displays anti-fibrotic properties that limit fibrosis. Phosphodiesterases (PDEs) metabolize cAMP and thus regulate cAMP signaling. While some existing therapies inhibit PDEs, there are only broad family specific inhibitors. The understanding of cAMP signaling compartments, some centered around lipid rafts/caveolae, has led to interest in defining how specific PDE isoforms maintain these signaling microdomains. The possible altered expression of PDEs, and thus abnormal cAMP signaling, in obstructive lung diseases has been poorly explored. We propose that inhibition of specific PDE isoforms can improve therapy of obstructive lung diseases by amplifying specific cAMP signals in discreet microdomains.
Males are responsible for half or even more of all the primary causes of infertility and the exact etiology remains unknown in many cases. Medical treatment of Male Reproductive and Sexual Health for the most prevalent diseases in contemporary societies can affect male reproduction through central hormonal axis effects, direct gonadotoxic action and effects on sperm or sexual functions. Overall, many medications frequently prescribed can have adverse effects on male fertility; however, conclusive evidence in humans is often limited. In addition, anabolic steroids have received increased attention as drugs of abuse for gaining muscle mass and improving athletic performance among men and are commonly associated with infertility accompanied by oligo- or azoospermia with abnormalities in sperm motility and morphology. Most physicians do not properly counsel their patients about potential effects on their fertility, including for medications commonly prescribed on a day-to-day basis or for drugs of abuse such as anabolic steroids. This chapter aims to highlight the adverse effects of commonly used medications and specifically of anabolic steroids on male fertility.
Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent.
The most recently discovered 3′,5′-cyclic nucleotide phosphodiesterase family is the Phosphodiesterase 11 (PDE11) family, which is encoded by a single gene PDE11A. PDE11A is a dual-specific PDE, breaking down both cAMP and cGMP. There are four PDE11A splice variants (PDE11A1-4) with distinct tissue expression profiles and unique N-terminal regulatory regions, suggesting that each isoform could be individually targeted with a small molecule or biologic. PDE11A4 is the PDE11A isoform expressed in brain and is found in the hippocampal formation of humans and rodents. Studies in rodents show that PDE11A4 mRNA expression in brain is, in fact, restricted to the hippocampal formation (CA1, possibly CA2, subiculum, and the adjacently connected amygdalohippocampal area). Within the hippocampal formation of rodents, PDE11A4 protein is expressed in neurons but not astrocytes, with a distribution across nuclear, cytoplasmic, and membrane compartments. This subcellular localization of PDE11A4 is altered in response to social experience in mouse, and in vitro studies show the compartmentalization of PDE11A4 is controlled, at least in part, by homodimerization and N-terminal phosphorylation. PDE11A4 expression dramatically increases in the hippocampus with age in the rodent hippocampus, from early postnatal life to late aging, suggesting PDE11A4 function may evolve across the lifespan. Interestingly, PDE11A4 protein shows a three to tenfold enrichment in the rodent ventral hippocampal formation (VHIPP; a.k.a. anterior in primates) versus dorsal hippocampal formation (DHIPP). Consistent with this enrichment in VHIPP, studies in knockout mice show that PDE11A regulates the formation of social memories and the stabilization of mood and is a critical mechanism by which social experience feeds back to modify the brain and subsequent social behaviors. PDE11A4 likely controls behavior by regulating hippocampal glutamatergic, oxytocin, and cytokine signaling, as well as protein translation. Given its unique tissue distribution and relatively selective effects on behavior, PDE11A may represent a novel therapeutic target for neuropsychiatric, neurodevelopmental, or age-related disorders. Therapeutically targeting PDE11A4 may be a way to selectively restore aberrant cyclic nucleotide signaling in the hippocampal formation while leaving the rest of the brain and periphery untouched, thus, relieving deficits while avoiding unwanted side effects.
Objectives:
To investigate the effect of chronic daily administration of different doses of tadalafil on the structure of the seminiferous tubules and on spermatogenesis.
Methods:
Sixty adult male wistar rats were included, they were divided into four groups: a control group (group I) and groups II, III, IV that received daily tadalfil in doses of 0.45, 0.9, 1.8 mg/kg for twelve weeks (equivalent to human doses of 5, 10, 20 mg daily) respectively. The epididymis was processed for evaluation of sperm parameters, serum testosterone was measured, Johnsen score for rats was calculated and testicular histopathological and ultrastructural examinations were performed.
Results:
Serum testosterone was significantly lower in group IV than in groups I and II. Moreover, post-treatment values in group IV were significantly lower than pre-treatment values. A significant decline in sperm motility and morphology was detected in groups III and IV compared to groups I and II. Sperm count was significantly lower in group IV compared to the other groups. Johnsen score was significantly lower in groups III and IV compared to groups I and II and in group IV compared to group III. In addition, histopathological and ultrastructural degenerative changes in rat testes were detected these changes were dose-dependent and increased with increasing the dose of tadalafil.
Conclusions:
Chronic daily oral administration of tadalafil to male albino rats demonstrate a dose-dependent alteration to testicular histology and semen parameters. The influence of these changes on the actual fertility of these animals remains to be determined.
This chapter focuses on the atomic structures of cGMP- or cAMP-binding GAF domains from the PDEs and adenylyl cyclases. These include the X-ray crystal structures of the regulatory segments, consisting of tandem GAF domains, from the mammalian phosphodiesterase PDE2A, and from a cyanobacterial adenylyl cyclase. cAMP and cGMP are important second messengers in cells. Their levels are controlled by activities of adenylyl and guanylyl cyclases (AC or GC), the enzymes that catalyze their synthesis, and cyclic nucleotide phosphodiesterases (PDEs), which hydrolyze these 3',5' cyclic nucleotides to their inactive 5'-nucleotide monophosphates. Of the 11 PDE families identified in mammalian tissues, all contain an N-terminal regulatory segment and a C-terminal catalytic domain. The first crystal structures of cyclic nucleotide-binding GAF domains have answered several basic questions about the mode of ligand binding and dimerization, but have also raised many others. A putative GAF ligand was found when the cAMP-stimulated cyanobacterial adenylyl cyclase cyaB1 was shown to be negatively regulated through its GAF domains by Na+, with an IC50 of 14.3 mM. Ultimately, crystal or NMR structures will be needed for the various PDE domains with and without bound ligands to visualize the conformational changes that occur upon binding. Structures of the full-length holoenzymes may also be required to visualize the allosteric mechanism. Since these small molecule binding GAF domains are intimately involved in regulation of so many different enzymes, they are also likely to become good targets for drug development.
During the 50 years since their discovery, the cyclic nucleotide phosphodiesterases (PDEs) have emerged as a major modulator of hormone and neurotransmitter signaling. A large number of genes and splicing variants have been described, suggesting complexity and highly specialized functions within the cell. PDEs are now recognized as critical because they are involved in the termination and control of signal propagation as well as formation of microdomains of signaling. This chapter will provide an overview of the distribution and function of the cyclic nucleotide phosphodiesterase superfamily in the central nervous system (CNS) and will discuss current information related to the sequence homology, substrate specificity, and kinetic properties of PDEs.
Introduction:
Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. Areas covered: This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. Expert opinion: Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well-tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated.
Asthma, like many inflammation related disorders, has a complex etiology. Drugs targeting multiple pathways may prove more efficacious in these complex disorders. Cyclic 3′,5′-adenosine monophosphate (cAMP) phosphodiesterase IV (PDE IV) is one of the validated targets in bronchial asthma and despite availability of some therapeutic molecules targeting PDE-IV, molecules with better properties are desired. Eosinophil/neutrophil infiltration into lung may also be an important component of bronchial asthma in which increased expression of epithelial cell adhesion molecules may play an important role. This study describes the synthesis of a novel class of compounds ‘triazine-aryl-bis-indoles’ having a catechol derived structure constituting a part of ‘triazine’ and a part of ‘bis-indole’ moiety on it. This class of molecules potently inhibited both phosphodiesterase IV and expression of cell adhesion molecules ICAM-1 and VCAM-1. The best molecule of this class (Compound 11) inhibited PDE-IV activity in vitro, with an IC50 value of 14 µM compared to 12.7 µM for an existing drug rolipram. The compound 11 not only stabilized the cAMP level in human lung epithelial cells (L132) following stimulation with forskolin, but also inhibited TNF-α induced expression of cell adhesion molecules such as ICAM-1 and VCAM-1in human umbilical vein epithelial cells (HUVECs). It also significantly inhibited the adhesion of human neutrophils to the endothelial monolayer (IC50=17.86 µM) in a dose dependent manner. Its absolute bioavailability (in mice) was found to be 70% and its toxicity and pharmacokinetic profiles are excellent. The dual activity of this class of molecules suggests that this class of molecules could have broad therapeutic applications in neutrophil dominant diseases such as severe asthma, COPD and acute lung injury.
An increasing number of patients require long-term medication regimens at a young age, but the adverse effects of medications on male reproduction are often inadequately considered, recognized and investigated. Medications can affect male reproduction through central hormonal effects, direct gonadotoxic effects, effects on sperm function or on sexual function. For example, exogenous testosterone inhibits spermatogenesis through central suppression of the hypothalamic-pituitary-gonadal hormonal axis. 5α-reductase inhibitors can impair sexual function, decrease semen volume and negatively affect sperm parameters, depending on dose and treatment duration. α-Blockers might decrease seminal emission and cause retrograde ejaculation, depending on the receptor specificity and dose of the agent. Phosphodiesterase inhibitors seem to have variable effects based on the isoform inhibited and evidence is conflicting. Antihypertensive and psychotropic agents can affect sperm, sexual function and hormonal parameters. For antibiotics, the literature on effects on sperm and sperm function is limited and dated. Many chemotherapeutic agents have a direct gonadotoxic effect, depending on agents used, dosing and number of treatment cycles. Overall, many medications commonly used in urology can have effects on male fertility (mostly reversible) but conclusive evidence in humans is often limited. Men should be counselled appropriately about potential drug-related adverse effects on their fertility.
The 11 cyclic nucleotide phosphodiesterase (PDE) families are differentially distributed in the brain, suggesting that they contribute in unique ways to central nervous system functions. Given that PDE1, PDE2, PDE4, PDE7, PDE9, and PDE10 are enriched in the hippocampus, amygdala, and neostriatum, they may contribute significantly in the mediation of memory. In this chapter, the roles of the different PDE families and their isoforms in mediating memory and the mechanisms involved are reviewed.
Purpose: The purpose of this study was to describe the current phosphodiesterase type 5 (PDE5) inhibitors and their use in the oral pharmacotherapy of male erectile dysfunction and other andrological maladies (such as Peyronie’s disease, premature ejaculation, benign prostatic hyperplasia and infertility). Methods: A survey of the literature was conducted to summarize data from basic research and clinical studies on the use of the orally active PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) in the treatment of andrological maladies, including male erectile dysfunction, Peyronie’s disease, premature ejaculation, benign prostatic hyperplasia, and infertility. Results: The information currently available has played a significant role in promoting the concept of inhibiting the cyclic GMP-specific PDE5 to treat male and female sexual dysfunction. PDE5 inhibitors are regarded as efficacious; they combine a high response rate with the advantage of an on-demand intake and have a fast onset of action and an improved effect-to-side-effect ratio. Basic research on peripheral intracellular signal transduction in penile vascular and nonvascular erectile tissue has provided the basis for the development and introduction of new therapeutic modalities (including new PDE5 inhibitors) for the management of disturbances of male sexual function, some of which have already been offered to patients. Conclusion: As the concept of taking a pill as a cure for the relief of symptoms has become widely accepted among consumers, pharmacological treatment of male sexual dysfunction will continue to focus on selective, orally available drugs that influence peripheral intracellular or central targets.
Effects of acute tadalafil on sperm motility and acrosome reaction were investigated, both in vitro and in vivo. Twenty asthenozoospermic and 20 normozoospermic patients as control were randomly enrolled. For in vitro part, 0.5 ml tadalafil solutions with different concentrations were added (0.2, 0.1, 0.05 and 0.025 μg ml(-1) , respectively) into semen samples. In both groups, samples treated with 0.2 μg ml(-1) tadalafil had significant increase in sperm motility after 2 h incubation. For in vivo part, oral administration of tadalafil (20 mg) or sildenafil (100 mg) was given. In both groups, computer-assisted semen analysis parameters showed no significant difference. After the administration of tadalafil (2 h) and sildenafil (1 h), there was no significant difference observed in premature acrosome reaction incidence rate. Taking both in vitro and in vivo results into consideration, acute on-demand administration of tadalafil would have no adverse effect on semen parameters.
Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.
Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene‐related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies.
This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments.
The use of phosphodiesterase-5 inhibitors has become the first-line treatment of erectile dysfunction nowadays. The daily application of tadalafil has become a line of treatment of other diseases such as pulmonary hypertension and cardiomyopathy. This study aimed at exploring whether the chronic use of tadalafil has an adverse effect on the testes and semen of old albino rats. Sixty male albino rats were divided into three groups. Group 1: given 2 ml saline orally for 90 days. Group 2: received tadalafil orally (1.8 mg kg(-1) day(-1) for 3 months equivalent to 20 mg day(-1) for 3 months as in human dose) and Group 3: received tadalafil orally (1.8 mg kg(-1) day(-1) for 6 months equivalent to 20 mg day(-1) for 6 months as in human dose). Animals were observed daily for signs of toxicity and mortality. Body weight and food consumption were recorded once a week. After sacrificing the animals, gross examination of the testes was performed in situ and then the epididymis was processed for the evaluation of sperm parameters and testes with other organs relative weight was calculated. Testicular histopathological examination was performed to evaluate microscopic changes in the seminiferous tubules. The mean testicular weight was significantly lower in animals of Group 3, and no significant changes were observed in Group 2. Sperm count showed a significant time-dependent decrease. Sperm motility decreased significantly in both groups with higher effect in Group 3. Incidence of abnormal forms increased in both groups (about 5 and 7 times in Group 2 and 3 respectively). Histological examination revealed mild changes in Group 2 and moderate changes in Group 3 in the form of loosely packed connective stroma around seminiferous tubules, reduction in number of spermatogenic cells with sloughing of many spermatocytes within the lumen of some tubules. Large vacuoles appeared in the tubules which contained a fewer number of sperm. Sperm bundles were degenerated in most tubules and completely absent in others. It is concluded that chronic daily use of tadalafil produces detrimental effects on the structure and function of the testes of old male albino rats which are duration dependent.
In a continuing effort to discover novel PDE5 inhibitors, we have successfully found quinazolines with 4-benzylamino substitution as potent and selective PDE5 inhibitors. Initial lead compound (1) was found to be easily metabolized when incubated with human liver microsomes mainly through C6 amide hydrolysis. Blocking of this metabolic hot spot led to discovery of 10 (CKD533) which is highly potent, selective and orally efficacious in conscious rabbit model for erectile dysfunction and now is undergoing preclinical toxicology study.
Alprostadil is approved for treatment of male erectile dysfunction (ED) by injection or urethral insertion. Topical delivery of alprostadil offers an improved alternative.
To evaluate the long-term safety and efficacy of topical alprostadil cream.
This was a multicenter, open-label, long-term study in 1,161 patients (998 double-blind rollover; 163 naïve) with ED. For the first 4 weeks, patients could administer eight doses of 200 mcg alprostadil to the penis meatus before intercourse (up to 2 per/week). Patients then self-selected to administer 300 or 100 mcg doses if hypo-responsive or hyper-responsive, respectively, or 200 mcg if no change, for up to 9 months (2 doses/week).
Safety evaluated patient/partner adverse events (AEs), changes in vital signs, clinical laboratory tests, physical examinations, and electrocardiograms. Efficacy assessed International Index of Erectile Function, Sexual Encounter Profile, Patient Self Assessment of Erection, and Global Assessment Questionnaire.
Approximately 12% of patients discontinued due to hypo-/hyper-responsiveness, 16% withdrew consent for a variety of reasons, and less than 5% discontinued because of AEs. The majority of patients (73%) selected 300 mcg alprostadil as the final dose. The most common AEs involved application site burning or erythema (12.2%), meatal or glans pain (4.4%), and prolonged or painful erection (1.3%). Only 5 (0.4%) patients reported a prolonged erection of >or=4 hours (priapism). Vaginal burning or itching (2.1%) was reported most frequently by partners. The majority of patients (74%) demonstrated an overall improvement in erectile function on most end-points, especially after adjusting dose strength to their individual responsiveness.
Topical alprostadil cream was considered effective and safe by most patients and their partners, with most AEs limited to the application site. Dose adjustment to 300 mcg alprostadil facilitated the greatest improvement in erectile function in the majority of patients. A separate report will integrate patient data from the open-label extension and prior double-blind studies.
In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
We report here the cloning, expression, and characterization of human PDE11A1, a member of a distinct cyclic nucleotide phosphodiesterase
(PDE) family. PDE11A exhibits ≤50% amino acid identity with the catalytic domains of all other PDEs, being most similar to
PDE5, and has distinct biochemical properties. The human PDE11A1 cDNA isolated contains a complete open reading frame encoding
a 490-amino acid enzyme with a predicted molecular mass of 55,786 Da. At the N terminus PDE11A1 has a single GAF domain homologous
to that found in other signaling molecules, including PDE2, PDE5, PDE6, and PDE10, which constitutes a potential allosteric
binding site for cGMP or another small ligand. Tissue distribution studies indicate that PDE11A mRNA occurs at highest levels
in skeletal muscle, prostate, kidney, liver, pituitary, and salivary glands and testis. PDE11A is expressed as at least three
major transcripts of ≈10.5, ≈8.5, and ≈6.0 kb, thus suggesting the existence of multiple subtypes. This possibility is further
supported by the detection of three distinct proteins of ≈78, ≈65, and ≈56 kDa by Western blotting of human tissues for PDE11A
isoforms. Recombinant human PDE11A1 hydrolyzes both cGMP and cAMP with Km values of 0.52 μM and 1.04 μM, respectively, and similar Vmax values. Therefore, PDE11A represents a dual-substrate PDE that may regulate both cGMP and cAMP under physiological conditions.
PDE11A is sensitive to the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) as well as zaprinast and dipyridamole,
inhibitors that are generally considered relatively specific for the cGMP-selective PDEs, with IC50 values of 49.8 μM, 12.0 μM, and 0.37 μM, respectively.
The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 microM for cGMP and 2.4 microM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialis, Lilly-ICOS), vardenafil (Levitra, Bayer-GSK), and sildenafil (Viagra, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.
Capacitation is defined as the series of transformations that spermatozoa normally undergo during their migration through the female genital tract, in order to reach and bind to the zona pellucida, undergo the acrosome reaction, and fertilize the egg. During this process, extensive changes occur in all sperm compartments (head and flagellum; membrane, cytosol, cytoskeleton), factors originating from epididymal fluid and seminal plasma are lost or redistributed and membrane lipids and proteins are reorganized; ion fluxes induce biochemical modifications and controlled amounts of reactive oxygen species are generated; spermatozoa develop hyperactivated motility; and complex signal transduction mechanisms are initiated. The main purpose of capacitation is to ensure that spermatozoa reach the eggs at the appropriate time and in the appropriate state to fertilize these eggs, by finely-controlling the rate of the changes necessary to prime spermatozoa and by activating all the mechanisms needed for the subsequent acrosome reaction. The reversibility of some of the mechanisms leading to sperm capacitation may therefore be a very important aspect of the fine regulation and perfect timing of this process.
We report here the cloning, expression, and characterization of human PDE11A1, a member of a distinct cyclic nucleotide phosphodiesterase (PDE) family. PDE11A exhibits </=50% amino acid identity with the catalytic domains of all other PDEs, being most similar to PDE5, and has distinct biochemical properties. The human PDE11A1 cDNA isolated contains a complete open reading frame encoding a 490-amino acid enzyme with a predicted molecular mass of 55,786 Da. At the N terminus PDE11A1 has a single GAF domain homologous to that found in other signaling molecules, including PDE2, PDE5, PDE6, and PDE10, which constitutes a potential allosteric binding site for cGMP or another small ligand. Tissue distribution studies indicate that PDE11A mRNA occurs at highest levels in skeletal muscle, prostate, kidney, liver, pituitary, and salivary glands and testis. PDE11A is expressed as at least three major transcripts of approximately 10.5, approximately 8.5, and approximately 6.0 kb, thus suggesting the existence of multiple subtypes. This possibility is further supported by the detection of three distinct proteins of approximately 78, approximately 65, and approximately 56 kDa by Western blotting of human tissues for PDE11A isoforms. Recombinant human PDE11A1 hydrolyzes both cGMP and cAMP with K(m) values of 0.52 microM and 1.04 microM, respectively, and similar V(max) values. Therefore, PDE11A represents a dual-substrate PDE that may regulate both cGMP and cAMP under physiological conditions. PDE11A is sensitive to the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) as well as zaprinast and dipyridamole, inhibitors that are generally considered relatively specific for the cGMP-selective PDEs, with IC(50) values of 49.8 microM, 12.0 microM, and 0.37 microM, respectively.
cDNAs encoding a novel phosphodiesterase, phosphodiesterase 11A (PDE11A), were isolated by a combination of reverse transcriptase-polymerase chain reaction using degenerate oligonucleotide primers and rapid amplification of cDNA ends. Their catalytic domain was identical to that of PDE11A1 (490 amino acids) reported during the course of this study. However, the cDNAs we isolated had N termini distinct from PDE11A1, indicating two novel N-terminal variants of PDE11A. PDE11A3 cDNA encoded a 684-amino acid protein including one complete and one incomplete GAF domain in the N-terminal region. PDE11A4 was composed of 934 amino acids including two complete GAF domains and shared 630 C-terminal amino acids with PDE11A3 but had a distinct N terminus containing the putative phosphorylation sites for cAMP- and cGMP-dependent protein kinases. PDE11A3 transcripts were specifically expressed in testis, whereas PDE11A4 transcripts were particularly abundant in prostate. Recombinant PDE11A4 expressed in COS-7 cells hydrolyzed cAMP and cGMP with K(m) values of 3.0 and 1.4 microm, respectively, and the V(max) value with cAMP was almost twice that with cGMP. Although PDE11A3 showed the same K(m) values as PDE11A4, the relative V(max) values of PDE11A3 were approximately one-sixth of those of PDE11A4. PDE11A4, but not PDE11A3, was phosphorylated by both cAMP- and cGMP-dependent protein kinases in vitro. Thus, the PDE11A gene undergoes tissue-specific alternative splicing that generates structurally and functionally distinct gene products.
Phosphodiesterase 11A (PDE11A) is a recently identified family of cAMP and cGMP hydrolyzing enzymes. Thus far, a single splice variant designated as PDE11A1 has been reported. In this study, we identify and characterize two additional splice variants of PDE11A, PDE11A2 and PDE11A3. The full-length cDNAs are 2,141 bp for PDE11A2 and 2205 bp for PDE11A3. The ORF of PDE11A2 predicts a protein of 576 aa with a molecular mass of 65.8 kDa. The ORF of PDE11A3 predicts a protein of 684 aa with a molecular mass of 78.1 kDa. Comparison of the PDE11A2 sequence with that of PDE11A1 indicates an additional 86 aa at the N terminus of PDE11A2. Part of this sequence extends the potential cGMP binding region (GAF domain) present in PDE11A1. Compared with PDE11A2, PDE11A3 has an additional 108 N-terminal amino acids. Sequence analysis of PDE11A3 indicates the presence of another GAF domain in this region. This diversification of regulatory sequences in the N-terminal region of PDE11A splice variants suggests the interesting possibility of differential regulation of these enzymes. Recombinant PDE11A2 and -A3 proteins expressed in the Baculovirus expression system have the ability to hydrolyze both cAMP and cGMP. The K(m) values for cAMP hydrolysis are 3.3 microM and 5.7 microM for PDE11A2 and PDE11A3, respectively. The K(m) values for cGMP hydrolysis are 3.7 microM and 4.2 microM for PDE11A2 and PDE11A3, respectively. Both PDEs showed a V(max) ratio for cAMP/cGMP of approximately 1.0. PDE11A2 is sensitive to dipyridamole, with an IC(50) of 1.8 microM, and to zaprinast, with an IC(50) of 28 microM. PDE11A3 demonstrated similar pattern of inhibitor sensitivity with IC(50) values of 0.82 and 5 microM for dipyridamole and zaprinast, respectively.
cGMP-specific, cGMP-binding phosphodiesterase (PDE5) regulates such physiological processes as smooth muscle relaxation and neuronal survival. PDE5 contains two N-terminal domains (GAF A and GAF B), but the functional roles of these domains have not been determined. Here we show that recombinant PDE5 is activated directly upon cGMP binding to the GAF A domain, and this effect does not require PDE5 phosphorylation. PDE5 exhibited time- and concentration-dependent reversible activation in response to cGMP, with the highest activation (9- to 11-fold) observed at low substrate concentrations (0.1 micro M cGMP). A monoclonal antibody directed against GAF A blocked cGMP binding, prevented PDE5 activation and decreased basal activity, revealing that PDE5 in its non-activated state has low intrinsic catalytic activity. Activated PDE5 showed higher sensitivity towards sildenafil than non-activated PDE5. The stimulatory effect of cGMP binding on the catalytic activity of PDE5 suggests that this mechanism of enzyme activation may be common among other GAF domain-containing proteins. The data also suggest that development of agonists and antagonists of PDE5 activity based on binding to this site might be possible.
In platelets, the nitric oxide (NO)-induced cGMP response is indicative of a highly regulated interplay of cGMP formation and cGMP degradation. Recently, we showed that within the NO-induced cGMP response in human platelets, activation and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains. The reversal of activation was slow, and was not completed after 60 min. Phosphorylation enhanced the cGMP-induced activation, allowing it to occur at lower cGMP concentrations. Also, in intact platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was detected. Finally, the long-term desensitization of the cGMP response induced by a low NO concentration reveals the physiological relevance of the PDE5 activation within NO/cGMP signaling. In sum, we suggest NO-induced activation and phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback loop shaping the cGMP response in human platelets in order to adapt to the amount of NO available.
Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of enzymes (PDE1-PDE11) which hydrolyse cyclic AMP and cyclic GMP to their biologically inactive 5' derivatives. Cyclic AMP is an important physiological amplifier of glucose-induced insulin secretion. As PDEs are the only known mechanism for inactivating cyclic nucleotides, it is important to characterise the PDEs present in the pancreatic islet beta cells. Several studies have shown pancreatic islets or beta cells to contain PDE1C, PDE3B and PDE4, with some evidence for PDE10A. Most evidence suggests that PDE3B is the most important in relation to the regulation of insulin release, although PDE1C could have a role. PDE3-selective inhibitors augment glucose-induced insulin secretion. In contrast, activation of beta-cell PDE3B could mediate the inhibitory effect of IGF-1 and leptin on insulin secretion. In vivo, although PDE3 inhibitors augment glucose-induced insulin secretion, concomitant inhibition of PDE3B in liver and adipose tissue induce insulin resistance and PDE3 inhibitors do not induce hypoglycaemia. The development of PDE3 inhibitors as anti-diabetic agents would require differentiation between PDE3B in the beta cell and that in hepatocytes and adipocytes. Through their effects in regulating beta-cell cyclic nucleotide concentrations, PDEs could modulate beta-cell growth, differentiation and survival; some work has shown that selective inhibition of PDE4 prevents diabetes in NOD mice and that selective PDE3 inhibition blocks cytokine-induced nitric oxide production in islet cells. Further work is required to understand the mechanism of regulation and role of the various PDEs in islet-cell function and to validate them as targets for drugs to treat and prevent diabetes.
Cyclic AMP (cAMP) and cGMP regulate a myriad of cellular functions, such as metabolism, contractility, motility, and transcription in virtually all cell types, including those of the cardiovascular system. Considerable effort over the last 20 years has allowed identification of the cellular components involved in the synthesis of cyclic nucleotides, as well as effectors of cyclic nucleotide-mediated signaling. More recently, a central role for cyclic nucleotide phosphodiesterase (PDE) has also been elaborated in many cell types, including those involved in regulating the activities of the cardiovascular system. In this review, we introduce the PDE families whose members are expressed in cells of the cardiovascular system including cardiomyocytes, vascular smooth muscle cells, and vascular endothelial cells. Because cell behavior is a dynamic process influenced by numerous factors, we will attempt to emphasize how changes in the activity, expression, and targeting of PDE influence cyclic nucleotide-mediated regulation of the behavior of these cells.
Cyclic nucleotide phosphodiesterase 11A (PDE11A) is the newest member in the PDE family. Although the tissue distribution of PDE11A mRNA has been shown, its protein expression pattern has not been well studied. The goal of this report is to investigate the distribution of PDE11A proteins in a wide range of normal and malignant human tissues. We utilized a polyclonal antibody that recognized all four PDE11A isoforms. Its specificity was demonstrated by Western blot analysis on a recombinant human PDE11A protein and native PDE11A proteins in various human tissues. Immunohistochemistry showed that PDE11A is widely expressed. Various degrees of immunoreactivity were observed in the epithelial cells, endothelial cells, and smooth muscle cells of all tissues examined. The highest expression was in the epithelial, endothelial, and smooth muscle cells of the prostate, Leydig, and spermatogenic cells of the testis, the tubule epithelial cells in the kidney, the epithelial and endothelial cells in the adrenal, the epithelial cells and macrophages in the colon, and the epidermis in the skin. Furthermore, PDE11A expression was also detected in several human carcinomas. Our results suggest that PDE11A might be involved in multiple physiological processes in various organs via its ability to modulate intracellular cAMP and cGMP levels.
PDE11A is a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE). Presently four unique variants carrying distinct GAF sequences in the N-terminal region have been identified. While human PDE11A3 and PDE11A4 are known to be specifically expressed in testis and prostate, respectively, PDE11A1 was mainly detected in skeletal muscle. The human PDE11A gene was investigated and revealed to span > 300 kb, contain 23 exons and be mapped on chromosome 2q31. The transcription start sites of PDE11A1, PDE11A3 and PDE11A4 were determined, and the promoter sequences were revealed. Although 5′ flanking genomic regions of PDE11A1 and PDE11A3 had a consensus TATA motif, that of PDE11A4 was a TATA-less but contained CCAAT box and Sp1-binding sequence. Interestingly, we found that the exon 2 sequence for N-terminal region of PDE11A3 encoded an N-terminal sequence of the cytochrome c pseudogene in an alternate reading frame, and that C-terminal region of the cytochrome c pseudogene in intron 2 was disrupted by the insertion of Alu repetitive sequence. Furthermore, we examined the exon–intron organization of the PDE2A gene and compared the exon organization among GAF-PDE family. The exon organization of the PDE11A catalytic domain was very similar to those of PDE5A and PDE6B. However, other GAF-PDEs, PDE2A and PDE10A, displayed different exon organization from PDE11A although these three PDEs are similar in their amino-acid sequences to each other. The findings suggested that PDE11A has a common ancestral gene with PDE5A and PDE6s, whereas PDE2A and PDE10A are generated separately from these three GAF-PDEs.
Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes including nuclear DNA compaction and acrosome formation. Transcription activator CREM (cyclic AMP-responsive element modulator) is highly expressed in postmeiotic cells, and CREM may be responsible for the activation of several haploid germ cell-specific genes involved in the structuring of the spermatozoon. The specific role of CREM in spermiogenesis was addressed using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium in mutant male mice reveals postmeiotic arrest at the first step of spermiogenesis. Late spermatids are completely absent, and there is a significant increase in apoptotic germ cells. We show that CREM deficiency results in the lack of postmeiotic cell-specific gene expression. The complete lack of spermatozoa in the mutant mice is reminiscent of cases of human infertility.
cGMP-binding phosphodiesterases contain two homologous allosteric cGMP-binding sites (sites a and b) that are arranged in tandem; they constitute a superfamily of mammalian cyclic nucleotide receptors distinct from the cyclic nucleotide-dependent protein kinases/cation channels family. The functional role of each of these two sites in the phosphodiesterases is not known. The cGMP-binding sites of one of these phosphodiesterases, the cGMP-binding cGMP-specific phosphodiesterase (cGB-PDE, PDE5), have been analysed by using site-directed mutagenesis. Mutations that affect cGMP binding to either one or both allosteric sites do not influence cGMP hydrolysis in the catalytic site under the conditions used. However, compared with wild-type enzyme, the D289A, D478A and D289A/D478A mutants, which are defective in cGMP binding to either site a or site b, or both allosteric sites, require much higher cGMP concentrations for the allosteric stimulation of phosphorylation by the catalytic subunit of cAMP-dependent protein kinase. The cGMP effect is on the cGB-PDE rather than on the catalytic subunit of the protein kinase because the latter enzyme does not require cGMP for activity. The D289N mutant, which has higher binding affinity for cGMP than does the wild-type enzyme, is phosphorylated at lower concentrations of cGMP than is the wild-type enzyme. It is concluded that cGMP binding to the allosteric sites of cGB-PDE does not directly affect catalysis, but binding to both of these sites regulates phosphorylation of this enzyme.
The cAMP signaling pathway is an important mediator of extracellular signals in organisms from prokaryotes to higher eukaryotes. In mammals two types of adenylyl cyclase synthesize cAMP; a ubiquitous family of transmembrane isoforms regulated by G proteins in response to extracellular signals, and a recently isolated soluble enzyme insensitive to heterotrimeric G protein modulation. Using the very sensitive reverse transcription-polymerase chain reaction (RT-PCR), soluble adenylyl cyclase (sAC) expression is detectable in almost all tissues examined; however, Northern analysis and in situ hybridization indicate that high levels of sAC message are unique to male germ cells. Elevated levels of sAC mRNA are first observed in pachytene spermatocytes and expression increases through spermiogenesis. The accumulation of high levels of message in round spermatids suggests sAC protein plays an important role in the generation of cAMP in spermatozoa, implying possible roles in sperm maturation through the epididymis, capacitation, hypermotility, and/or the acrosome reaction.
PDE11A is a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE). Presently four unique variants carrying distinct GAF sequences in the N-terminal region have been identified. While human PDE11A3 and PDE11A4 are known to be specifically expressed in testis and prostate, respectively, PDE11A1 was mainly detected in skeletal muscle. The human PDE11A gene was investigated and revealed to span > 300 kb, contain 23 exons and be mapped on chromosome 2q31. The transcription start sites of PDE11A1, PDE11A3 and PDE11A4 were determined, and the promoter sequences were revealed. Although 5' flanking genomic regions of PDE11A1 and PDE11A3 had a consensus TATA motif, that of PDE11A4 was a TATA-less but contained CCAAT box and Sp1-binding sequence. Interestingly, we found that the exon 2 sequence for N-terminal region of PDE11A3 encoded an N-terminal sequence of the cytochrome c pseudogene in an alternate reading frame, and that C-terminal region of the cytochrome c pseudogene in intron 2 was disrupted by the insertion of Alu repetitive sequence. Furthermore, we examined the exon-intron organization of the PDE2A gene and compared the exon organization among GAF-PDE family. The exon organization of the PDE11A catalytic domain was very similar to those of PDE5A and PDE6B. However, other GAF-PDEs, PDE2A and PDE10A, displayed different exon organization from PDE11A although these three PDEs are similar in their amino-acid sequences to each other. The findings suggested that PDE11A has a common ancestral gene with PDE5A and PDE6s, whereas PDE2A and PDE10A are generated separately from these three GAF-PDEs.
We have isolated and characterized rat cyclic nucleotide phosphodiesterase (PDE)11A, which exhibits properties of a dual-substrate PDE, and its splice variants (RNPDE11A2, RNPDE11A3, and RNPDE11A4). The deduced amino-acid sequence of the longest form of rat PDE11A splice variant, RNPDE11A4, was 94% identical with that of the human variant (HSPDE11A4). Rat PDE11A splice variants were expressed in a tissue-specific manner. RNPDE11A4 showed unique tissue distribution distinct from HSPDE11A4, which is specifically expressed in the prostate. Rat PDE11A splice variants were expressed in COS-7 cells, and their enzymatic characteristics were compared. Although the Km values for cAMP and cGMP were similar for all of them (1.3-1.6 and 2.1-3.9 microM, respectively), the Vmax values differed significantly (RNPDE11A4 > RNPDE11A2 > RNPDE11A3). Human PDE11A variants also displayed very similar Km values and significantly different Vmax values (HSPDE11A4 > HSPDE11A2 > HSPDE11A3 > HSPDE11A1). The Vmax values of HSPDE11A4 for cAMP and cGMP were at least 100 times higher than those of HSPDE11A1. These observations indicate unique characteristics of PDE11A splicing variants.
The SAR of a series of beta-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.
The advent of sildenafil (Viagra) for the treatment of erectile dysfunction has attracted widespread interests in phosphodiesterase type 5 (PDE5), the target of sildenafil, 1 and other members of the PDE superfamily. PDEs are intracellular enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By counterbalancing adenyl and guanyl cyclases, which catalyze the formation of cAMP and cGMP, respectively, PDEs serve to adjust the cellular concentrations of cAMP and cGMP, thereby influencing cellular functions. 2 In addition to sildenafil, hundreds of PDE inhibitors broadly or specifically target various PDE isoforms. Those with specificity and currently seeking approval from the United States Food and Drug Administration (FDA) or under clinical trials are the focus of this review. Emphasis is given to those with urologic applications (eg, erectile dysfunction and benign prostatic hyperplasia [BPH]-associated urinary dysfunction).
This review focuses primarily on our current understanding of the structure and function of GAF domains in cyclic nucleotide phosphodiesterases (PDEs). The GAF domain was originally identified by Aravind and Ponting ([1997][1]) using the position-specific iterative BLAST method (Altschul et al.,
Phosphodiesterases (PDEs) play a decisive role in cyclic nucleotide-mediated intracellular signaling. As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE inhibitor. Sildenafil, vardenafil, and tadalafil are selective for PDE5, with vardenafil exhibiting the highest potency and minimal inhibition of other PDEs, with the exception of PDE6. Tadalafil is extremely selective for PDE5, but also potently inhibits PDE11, an enzyme with unknown physiological function. As PDE1 is expressed in the brain, myocardium, and vascular smooth muscle cells, nonselectivity with respect to this enzyme (selectivity: tadalafil>vardenafil>sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil>vardenafil congruent with sildenafil), which is expressed only in retina and functions in visual transduction, can transiently disturb vision. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic guanosine monophospate levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.
Fertilization is well correlated with sperm concentration, rate of forward motility, and percentage of live, uncapacitated ejaculated spermatozoa, which is regulated in part by cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to their corresponding monophosphates, thereby counterbalancing the activities of cAMP and cGMP, and PDE11 is highly expressed in the testis, prostate, and developing spermatozoa. However, a physiological role of PDE11 is not known. We generated PDE11 knockout (PDE11-/-) mice to investigate the role of PDE11 in spermatozoa physiology. Ejaculated sperm from PDE11-/- mice displayed reduced sperm concentration, rate of forward progression, and percentage of live spermatozoa. Pre-ejaculated sperm from PDE11-/- mice displayed increased premature/spontaneous capacitance. These data are consistent with human data and suggest a role for PDE11 in spermatogenesis and fertilization potential. This is the first phenotype described for the PDE11-/- mouse and the first report of a physiological role for PDE11.
3',5'-Cyclic nucleotide phosphodiesterase 11 (PDE11) is the most recently discovered family of human 3',5'-cyclic nucleotide phosphodiesterases (PDEs). This family contains one gene, PDE11A, with four splice variants (PDE11A1-PDE11A4). The physiological role of PDE11A has not been determined. Tadalafil (Cialis), a PDE5A inhibitor used for the treatment of male erectile dysfunction, has been reported to partially inhibit PDE11. It was therefore of interest to consider the pattern of expression of PDE11 in human tissues. Although four PDE11A mRNA transcripts have been reported, we detected protein corresponding to only one of them, PDE11A4, in human prostate, pituitary, heart and liver. Using immunohistochemistry, there was strong PDE11A antibody staining in the glandular epithelium of the prostate and weak staining of neuronal cells within parasympathetic ganglia in the heart. No PDE11A protein was detected in blood vessels or cardiac myocytes. None of the four potential PDE11A proteins were detected in human skeletal muscle, testis, or penis.
To critically review the literature on vardenafil in the treatment of erectile dysfunction while integrating the clinical findings with the personal experience of the authors.
Analysis of published full-length papers that were identified through Medline search from January 2000 through May 2004. Abstracts published in peer-reviewed journals from the same period were also considered.
Efficacy, tolerability and safety, as reported in the peer-reviewed literature compares well with the authors' personal experience. Authors' personal observations include discussions on potency, selectivity, selection of initial dose, counselling for patients characteristically considered difficult-to-treat (diabetes, prostatectomy, depression), including the determination of the maximal efficacious dose and the possible role of daily dosing, optimisation of the use of vardenafil according to its pharmacokinetic and pharmacodynamic profiles (onset and reliability), and management of ED patients with or at risk for cardiovascular disease.
Extensive experience with vardenafil as reported in peer reviewed literature confirms the important role of vardenafil in the management of patients with ED. The development of each physician's own experience with vardenafil is key to optimise overall satisfaction of this therapy by the patient and his partner.
This study investigated the presence and function of intracellular cyclic nucleotide phosphodiesterases (PDEs) in mature mouse spermatozoa. PCR analysis detected gene transcripts for most of the 11 known PDE families in whole testis, but mainly for PDEs 1, 3, 6, and 8 in spermatozoa. Using specific antibodies, the strongest evidence was obtained for PDE proteins 1, 4, 6, 8, 10, and 11 in both sperm lysates and intact cells. These showed a range of subcellular localizations, with PDE 1A being primarily in the flagellum but PDEs 4D and 10A being in both the acrosomal region and the flagellum, similar to specific G proteins and adenylyl cyclases implicated in cAMP regulation during capacitation. In live spermatozoa, inhibitors selective for PDE 1 (MMPX) and 4 (rolipram) significantly increased cAMP over control levels but only rolipram significantly stimulated capacitation and in-vitro fertilizing ability; this suggests that compartmentalization has functional implications since only PDE 4 was abundant in both head and flagellum. Treatment of spermatozoa with CGS 21680, a stimulatory adenosine receptor agonist, significantly reduced cAMP-PDE activity at the same time-point when it causes increased cAMP. Thus, certain receptor-regulated cAMP processes in spermatozoa may be controlled by changes in both PDE and cyclase activities. In addition to demonstrating for the first time that some of the more recently discovered PDE isoforms, including PDE 6 (usually associated with the retina), are present in mature spermatozoa, this study provides clear evidence that the intracellular location of specific PDEs has important functional significance during capacitation and fertilization.
For Abstract see ChemInform Abstract in Full Text.
We assessed the effects on spermatogenesis of placebo vs 10 or 20 mg tadalafil administered daily for 6 months to healthy men and men with mild erectile dysfunction.
In 2 studies 421 healthy men or men with mild erectile dysfunction who were 45 years or older and met semen criteria derived from WHO reference values were randomized to 6 months of treatment with placebo (101) or 10 mg tadalafil (103), or to placebo (106) or 20 mg tadalafil (111). Semen samples and serum for reproductive hormones (testosterone, luteinizing hormone and follicle-stimulating hormone) were collected at baseline, after 3 months and at the end of treatment.
Tadalafil had no adverse effects on spermatogenesis, as assessed by sperm concentration, sperm count per ejaculate, percent sperm motility, normal morphology or serum reproductive hormones. Tadalafil was well tolerated. Common adverse events were headache, dyspepsia and back pain.
Chronic daily administration of tadalafil at doses of 10 and 20 mg for 6 months had no adverse effects on spermatogenesis or on reproductive hormones in men older than 45 years.
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