Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of cAMP and cGMP phosphodiesterases (EC 3.1.4.1), adenylate cyclase (EC 4.6.1.1) and protein carboxyl-methylase (EC 2.1.1.24) were measured in the particulate and soluble (105 000 g supernatant) fractions of washed spermatozoa isolated from five segments of the adult rat epididymis. The activities of both phosphodiesterases decreased during epididymal transit, whereas adenylate cyclase and protein carboxyl-methylase underwent a progressive increase, the latter showing the most marked alteration. Both cAMP and cGMP phosphodiesterases as well as the adenylate cyclase were all associated primarily with the particulate fraction, and the extent to which these enzymes were associated with the membranes increased as the spermatozoa passed through the epididymis. Sperm protein carboxyl-methylase activity was, on the other hand, predominantly soluble in all segments of the epididymis. Adenylate cyclase, cAMP phosphodiesterase and protein carboxyl-methylase activities were found predominantly in the sperm tails, whereas cGMP phosphodiesterase was equally distributed between heads and tails. These observations imply that the acknowledged increase in intracellular cAMP levels which occurs in spermatozoa during epididymal transit may be a consequence of both increased synthesis (adenylate cyclase) and reduced hydrolysis (phosphodiesterase).
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PMID:Rat sperm enzymes during epididymal transit. 628 32

A basic protein of apparent molecular weight 15 kD, designated bSVSP15, was purified from bovine seminal vesicle secretion to homogeneity, employing affinity absorption to calmodulin-Sepharose and reverse-phase HPLC. Immunoblotting identified bSVSP15 in bovine seminal plasma and seminal vesicle secretion, but it was not present either in extracts of bovine ampulla, epididymis, and testis or in serum or follicular fluid. When added to cAMP phosphodiesterase, bSVSP15 inhibited the activation of enzymatic activity by calmodulin in a reversible manner. Immunoscreening of a lambda gt11 expression cDNA library from bovine seminal vesicle tissue yielded two positive clones, pSVS4 and pSVS5, which were characterized by sequencing. Both sequences are identical, except for the 3' region. Because the derived amino acid sequence comprises, with an identity of 81%, the amino-terminal 21 residues of bSVSP15, cDNA clones pSVS4 and pSVS5 represent bSVSP15-specific mRNAs. The mature protein bSVSP15 contains 101 residues and is preceded by 25 residues of a signal sequence, characteristic for secretory proteins. Northern analysis identified two bSVSP15-specific mRNAs of 900 bp and 1200 bp, respectively. Sequence comparison yielded high homologies to human C-type natriuretic peptide. We conclude from this result that bSVSP15 is identical with the hitherto unknown bovine C-type natriuretic peptide.
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PMID:cDNA cloning identified a calmodulin-binding protein in bovine seminal plasma as bovine C-type natriuretic peptide. 801 Nov 67

Many developmentally regulated membrane proteins of lymphocytes are ecto-enzymes, with their active sites on the external surface of the cell. These enzymes commonly have peptidase, phosphodiesterase or nucleotidase activity. Their biological roles are just beginning to be discovered. Although their expression is usually associated with particular stages of lymphoid differentiation, the same gene products are often expressed on the surface of certain non-lymphoid cell types outside the immune system, indicating that their functions cannot be unique to lymphocytes, nor can they be ubiquitous. The plasma cell membrane protein PC-1 (phosphodiesterase I; EC 3.1.4.1/nucleotide pyrophosphatase; EC 3.6.1.9), which was one of the first serological markers for lymphocyte subsets to be discovered, is a typical example. Within the immune system, PC-1 is confined to plasma cells, which represent about 0.1% of lymphocytes. However, PC-1 is also expressed on cells of the distal convoluted tubule of the kidney, chondrocytes, osteoblasts, epididymis and hepatocytes. Recent work has shown that PC-1 is a member of a multigene family of ecto-phosphodiesterases that currently has two other members, PD-1 alpha (autotaxin) and PD-1 beta (B10). Within this family, the extracellular domains are highly conserved, especially around the active site. In contrast, the transmembrane and cytoplasmic domains are highly divergent. Individual members of the eco-phosphodiesterase family have distinct patterns of distribution in different cell types, and even within the same cell. For example, PC-1 is present only on the basolateral surface of hepatocytes, while B10 (PD-1 beta) is confined to the apical surface. Analysis of conservation and differences in the sequence of their cytoplasmic tails may illuminate intracellular targetting signals. Ecto-phosphodiesterases may play a part in diverse activities in different tissues, including recycling of nucleotides. They may also regulate the concentration of pharmacologically active extracellular compounds such as adenosine or its derivatives and cell motility. Some members may modulate local concentrations of pyrophosphate, and hence influence calcification in bone and cartilage.
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PMID:Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells: structure and function of the PC-1 family. 955 61

Small membranous vesicles, between 25- and 75-nm diameter, were collected by high-speed centrifugation from the ram cauda epididymal fluid and were found to be normal constituents of this fluid and of the seminal plasma. The SDS-PAGE protein pattern of these vesicles was specific and very different from that of the caudal fluid, seminal plasma, sperm extract, and cytoplasmic droplets. After two-dimensional electrophoresis separation and mass spectrometry analysis, several proteins were identified and grouped into i) membrane-linked enzymes, such as dipeptidyl peptidase IV (DPP-IV), neprilysin (NEP), phosphodiesterase-I (E-NPP3), and protein G-beta; ii) vesicle-associated proteins, such as lactadherin (MFEG8-PAS6/7) and vacuolar ATPase; iii) several cytoskeleton-associated proteins, such as actin, ezrin and annexin; and iv) metabolic enzymes. The presence of some of these proteins as well as several different hydrophobic proteins secreted by the epididymis was further confirmed by immunoblotting. These markers showed that the majority of the vesicles originated from the cauda epididymal region. The physical and biochemical characteristics of these vesicles suggest they are the equivalent of the exosomes secreted by several cell types and epithelium. The main membrane-linked proteins of the vesicles were not retrieved in the extract from cauda or ejaculated sperm, suggesting that these vesicles did not fuse with sperm in vivo.
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PMID:Identification, proteomic profiling, and origin of ram epididymal fluid exosome-like vesicles. 1563 28

This study investigated the testicular changes in the rat induced by the nonspecific phosphodiesterase inhibitor, theophylline using magnetic resonance microscopy (MRM) and ubiquitin immunostaining techniques. In vivo T1- and T2-weighted images were acquired at 2 T under anesthesia. Increased signal observed in the theophylline-treated rats suggests that leakage of MRM contrast was occurring. In vivo MRM results indicate that day 16 testis displayed an increased T1-weighted water signal in the area of the seminiferous tubule that decreased by day 32. These findings were validated by histopathology, suggesting that in vivo MRM has the sensitivity to predict changes in testis and epididymal tissues. The participation of the ubiquitin system was investigated, using probes for various markers of the ubiquitin-proteasome pathway. MRM can be used to detect subtle changes in the vascular perfusion of organ systems, and the up-regulation/mobilization of ubiquitin-proteasome pathway may be one of the mechanisms used in theophylline-treated epididymis to remove damaged cells before storage in the cauda epididymis. The combined use of in vivo MRM and subsequent tissue or seminal analysis for the presence of ubiquitin in longitudinal studies may become an important biomarker for assessing testis toxicities drug studies.
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PMID:Reproductive cytotoxicity is predicted by magnetic resonance microscopy and confirmed by ubiquitin-proteasome immunohistochemistry in a theophylline-induced model of rat testicular and epididymal toxicity. 1607 14

Aging of the male reproductive system leads to changes in endocrine signaling and is frequently associated with the emergence of prostate hyperplasia and bladder dysfunctions. Recent reports highlight prostate and bladder as promising targets for therapeutic interventions with inhibitors of the cyclic GMP (cGMP)-degrading phosphodiesterase 5 (PDE5). However, the cGMP signaling system in these organs is as yet poorly characterized, and the possibility of age-related alterations has not been addressed. This study investigates key proteins of cGMP pathways in bladder, prostate, and epididymis of young (3 months) and old (23-24 months) Wistar rats. Local differences in the abundance of PDE5, soluble guanylyl cyclase (sGC) and particulate guanylyl cyclases (GC-A, GC-B), endothelial nitric oxide synthase, and cGMP-dependent protein kinase I (PRKG1 (cGKI)) revealed pronounced tissue-specific peculiarities. Although cGMP-generating enzymes were not affected by age in all organs, we recognized age-related decreases of PDE5 expression in bladder and a selective diminishment of membrane-associated PRKG1 in epididymis. In disagreement with published data, all cGMP pathway proteins including PDE5 are poorly expressed in prostate. However, prostatic PRKG1 expression increases with aging. Androgen withdrawal during temporary Leydig cell elimination induced a massive (>12-fold) upregulation of PRKG1 in prostate but not in other (penis and epididymis) androgen-dependent organs. These findings identify PRKG1 as a key androgen-sensitive signaling protein in prostate of possible importance for growth regulation. The elucidated effects may have significance for age-associated pathologies in the male lower-urinary tract.
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PMID:Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion. 2151 85

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.
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PMID:Effects of chronic tadalafil use on the testes and sperm parameters of old albino rats. 2176 89

Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.
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PMID:Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas. 2319 97

The well orchestrated function of epididymal smooth muscle cells ensures transit of spermatozoa through the epididymal duct during which spermatozoa acquire motility and fertilizing capacity. Relaxation of smooth muscle cells is mediated by cGMP signaling and components of this pathway are found within the male reproductive tract. Whereas contractile function of caudal parts of the rat epididymal duct can be examined in organ bath studies, caput and corpus regions are fragile and make it difficult to mount them in an organ bath. We developed an ex vivo time-lapse imaging-based approach to investigate the contractile pattern in these parts of the epididymal duct. Collagen-embedding allowed immobilization without impeding contractility or diffusion of drugs towards the duct and therefore facilitated subsequent movie analyses. The contractile pattern was made visible by placing virtual sections through the acquired image stack to track wall movements over time. By this, simultaneous evaluation of contractile activity at different positions of the observed duct segment was possible. With each contraction translating into a spike, drug-induced alterations in contraction frequency could be assessed easily. Peristaltic contractions were also detectable and throughout all regions in the proximal epididymis we found regular spontaneous contractile activity that elicited movement of intraluminal contents. Stimulating cGMP production by natriuretic peptide ANP or inhibiting degradation of cGMP by the phosphodiesterase 5 inhibitor sildenafil significantly reduced contractile frequency in isolated duct segments from caput and corpus. RT-PCR analysis after laser-capture microdissection localized the corresponding molecules to the smooth muscle layer of the duct. Our time-lapse imaging approach proved to be feasible to assess contractile function in all regions of the epididymal duct under near physiological conditions and provides a tool to evaluate acute (side) effects of drugs and to investigate various signaling pathways.
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PMID:Time-lapse imaging as a tool to investigate contractility of the epididymal duct--effects of cGMP signaling. 2466 87

Soluble (cytosolic) forms of adenylyl cyclases (sAC), the enzymes catalyzing the conversion of ATP to the second messenger cAMP, play a key role in the regulation of spermatogenesis, control maturation of spermatozoa in the epididymis and their capacitation in the female genital tract, which determines their ability to fertilize. In the last years the significant progress was made in the study of the structural and functional organization and regulatory properties of sAC, their localization in the spermatozoa as well as in the investigation of intracellular cascades functionally coupled with sAC, including protein kinase A, cAMP-dependent phosphodiesterase, non-receptor tyrosine kinases, tyrosine phosphatases, transcription factors of CREB/CREM-family. The molecular mechanisms involved in the regulation of the intracellular concentration of bicarbonate anions, the main endogenous activators of sAC, were deciphered. Many evidences were obtained that the decrease of functional activity of sAC and signaling cascades and effector proteins coupled to it, as well as bicarbonate anion transporters lead to disturbances of spermatogenesis. As a consequence, the development of approaches for controlling the activity of sAC in spermatozoa is one of the priority ways to treat dysfunctions of the male reproductive system. Present review is devoted to advances in the study of soluble forms of AC and functionally coupled to them signaling cascades and effector proteins in the spermatozoa, as well as to the unresolved issues in this area.
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PMID:[Soluble forms of adenylyl cyclases of spermatozoa]. 2550 40


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