Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stanniocalcin (STC) is a recently discovered mammalian hormone that is widely distributed in many tissues. In rodents the STC gene is most highly expressed in ovary, specifically in androgen-producing thecal and interstitial cells. In addition, ovarian levels of expression rise 15-fold over pregnancy. The objective of this study was to develop a primary culture system for ovarian thecal-interstitial cells (TICs) to identify factors governing STC production and release. We used highly purified primary cultures of rat and bovine TICs, the purity of which was routinely assessed with antigenic and enzymatic markers. The functionality of cells was assured by their responsiveness to LH in the form of progesterone release. We found that forskolin significantly increased STC gene expression and secretion by both rat and bovine TICs, an effect that was only replicated by human (h) chorionic gonadotropin (CG). Coincubation of TICs with hCG and phosphodiesterase inhibitors further increased STC secretion, whereas coincubation of TICs with hCG and protein kinase A inhibitors attenuated hCG-stimulated release. Intriguingly, ovarian STC proved to be substantially larger than the 50-kDa homodimer produced in most other tissues. These results indicate that ovarian STC is physically distinct, a feature that could explain its presence in serum during pregnancy and lactation.
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PMID:Ovarian stanniocalcin is structurally unique in mammals and its production and release are regulated through the luteinizing hormone receptor. 1223 4

Low temperatures slow down metabolism, partly because the kinetic energy of molecules is reduced and enzymes may be structurally impaired. We now report that relative to its maximal activity at 37 degrees C, adenylate cyclase (AC) still retained 25% functionality (determined as cyclic adenosine monophosphate [cAMP] production) at 4 degrees C in mouse Leydig tumor cells (MLTC-1) in response to 50 IU/L human chorionic gonadotropin (hCG), whereas steroidogenic acute regulatory (StAR) protein mRNA and testosterone production were completely impaired. The incubation of MLTC-1 with the phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine; IBMX) resulted in significantly increased intracellular cAMP concentration at all 3 temperatures, but this had no impact on testosterone production. AC, cAMP, and phosphodiesterase form an important intracellular second-messenger mechanism in many organisms, some that inhabit very low temperature niches. The cold-resistance of AC and phosphodiesterase may thus have evolved to cope with adverse conditions. Although hibernation may lead to decreased steroid hormone production, it is also likely that cold-mediated decreased steroid hormone production induces hibernation.
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PMID:Low temperature blocks the stimulatory effect of human chorionic gonadotropin on steroidogenic acute regulatory protein mRNA and testosterone production but not cyclic adenosine monophosphate in mouse Leydig tumor cells. 1528 Oct

To determine whether phosphodiesterase (PDE) 3 inhibitors prevent the resumption of meiosis by primate oocytes in vivo, rhesus macaques were stimulated to develop multiple preovulatory follicles by administering human recombinant gonadotropins, and follicles were aspirated 34 h after an ovulatory stimulus (human chorionic gonadotropin [hCG]). Monkeys received no further treatment (controls) or the PDE3 inhibitor ORG 9935 (a) exclusively in the periovulatory interval beginning 6-12 h prior to receiving hCG at 200 mg/kg every 12 h orally (PER200) or a 200 mg/kg oral loading dose followed by 50 mg/kg sc every 6 h (PER50) or (b) throughout the ovarian stimulation protocol with daily increases until a dose of 200 mg/kg bid was administered onward from the eighth day of ovarian stimulation (EXT200). The primary outcome was the number of oocytes that had resumed meiosis (germinal vesicle breakdown [GVBD]) at collection. At initial aspiration, 85% of oocytes recovered from control animals (n = 4) had progressed to GVBD compared with 53% (p<.01), 23% (p<.01), and 13% (p<.01) recovered from animals in the PER200 (n = 2), PER50 (n = 1) and EXT200 (n = 3) groups, respectively. Although spontaneous maturation of oocytes was observed during follow-up culture in the absence of ORG 9935, none of the oocytes in the PER50 or EXT200 underwent normal fertilization in vitro. These results demonstrate that the PDE3 inhibitor ORG 9935 blocks oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques and suggest that PDE3 inhibitors have potential clinical use as contraceptives in women.
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PMID:The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation during gonadotropin-stimulated ovarian cycles in rhesus macaques. 1563 77

Cyclic AMP (cAMP) is a second messenger that plays a critical role in follicular recruitment, development and luteinization in the mammalian ovary. The cellular level of cAMP is largely dependent on the activity of phosphodiesterase (PDE), which degrades cAMP into 5'-AMP. The present study was conducted to investigate the level of cAMP and the activity of cAMP-PDE in postnatal rats; immature rats during gonadotropin-primed follicular development, ovulation and luteinization; adult rats during normal estrous cycling; and aged rats that spontaneously developed persistent estrous (PE) by radioimmunoassay (RIA). All four rat models were confirmed by histological examination of one ovary and assayed using the other ovary by RIA. In the postnatal rats, the ovarian cAMP level was high on day 10 after birth, while ovarian cAMP-PDE activity was highest at 21 days of age. In the immature female rats, both the ovarian cAMP level and cAMP-PDE activity increased remarkably after treatment with equine chorionic gonadotropin (eCG), increased continuously 24 h after injection of human chorionic gonadotropin (hCG) for induction of ovulation and luteinization, and then declined significantly. In the adult rats during the normal estrous cycle, the ovarian cAMP levels were low on the day of estrus, and there were no significant changes in ovarian cAMP-PDE activity throughout the estrous cycle. In the PE rats, the ovarian cAMP levels were similar to those of the adult rats on the day of estrus but were lower than those on the other days of the estrous cycle; ovarian cAMP-PDE activity was lower than that in the adult rats on any day of the estrous cycle. Together, these findings indicate that the ovarian cAMP level and cAMP-PDE activity were regulated in a stage-dependent manner during ovarian follicular development, atresia and luteinization and providing evidences that cAMP and cAMP-specific PDEs are involved in these physiological processes.
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PMID:Changes of cyclic AMP levels and phosphodiesterase activities in the rat ovary. 1738 41

Human chorionic gonadotropin (HCG) plays a major role in early human development through a series of well recognized pregnancy-promoting actions that are exerted in the first trimester, including maternal recognition of pregnancy, enhancement of embryo implantation and survival, stimulation of trophoblast growth and differentiation, and prolongation of the functional life of the corpus luteum. Recent research indicates that HCG can exert significant pregnancy-promoting actions also in the remainder of pregnancy through its effect on the myometrium and on fetal membranes. In the myometrium, HCG promotes the inhibition of smooth muscle cell contractility through several mechanisms, including inhibition of gap junction formation, reduction of intracellular calcium concentration, increase in the expression of progesterone receptor, and an increase in the expression of phosphodiesterase 5 (PDE5), an enzyme controlling the intracellular levels of cGMP. This effect appears to be specific for PDE5 since it has not been found for other hormones potentially involved in pregnancy such as estrogen, progesterone and thyroid hormone. In fetal membranes, HCG can modulate expression of the inducible isoform of nitric oxide synthase (iNOS), as well as specific immunoregulatory cytokines such as the high mobility group box 1 (HMGB1) protein. This accumulating evidence suggests that HCG has a wide spread pregnancy-promoting actions that are exerted in various reproductive and gestational tissues.
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PMID:Pregnancy-promoting actions of HCG in human myometrium and fetal membranes. 1738 98

Human chorionic gonadotropin (hCG) was administered to mares in estrus with large, dominant ovarian follicles to initiate follicular and oocyte maturation. Follicular contents were collected at 0, 2, 4 and 6 h after hCG. Epiregulin, amphiregulin and phosphodiesterase (PDE) mRNA contents of granulosa cells (PDE 4D) were determined by reverse transcription and real-time PCR; PDE 3A mRNA content of single oocytes was determined similarly. Copy numbers of mRNA did not increase for PDE 3A or 4D over the time interval studied. Amounts of epiregulin and amphiregulin mRNA were correlated (r=0.98) when log transformed. Epiregulin and amphiregulin mRNA increased (P<0.01) from controls by 4 h after hCG administration, with amphiregulin increasing (P<0.01) by 2 h after hCG administration. Epiregulin and amphiregulin mRNA levels remained elevated (P<0.01) at 6h after hCG. These results indicate that EGF-like growth factors are likely paracrine mediators of the LH signal in the horse.
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PMID:Potential involvement of EGF-like growth factors and phosphodiesterases in initiation of equine oocyte maturation. 1750 86

Oocytes are held in meiotic arrest in prophase I until ovulation, when gonadotropins trigger a subpopulation of oocytes to resume meiosis in a process termed "maturation." Meiotic arrest is maintained through a mechanism whereby constitutive cAMP production exceeds phosphodiesterase-mediated degradation, leading to elevated intracellular cAMP. Studies have implicated a constitutively activated Galpha(s)-coupled receptor, G protein-coupled receptor 3 (GPR3), as one of the molecules responsible for maintaining meiotic arrest in mouse oocytes. Here we characterized the signaling and functional properties of GPR3 using the more amenable model system of Xenopus laevis oocytes. We cloned the X. laevis isoform of GPR3 (XGPR3) from oocytes and showed that overexpressed XGPR3 elevated intraoocyte cAMP, in large part via Gbetagamma signaling. Overexpressed XGPR3 suppressed steroid-triggered kinase activation and maturation of isolated oocytes, as well as gonadotropin-induced maturation of follicle-enclosed oocytes. In contrast, depletion of XGPR3 using antisense oligodeoxynucleotides reduced intracellular cAMP levels and enhanced steroid- and gonadotropin-mediated oocyte maturation. Interestingly, collagenase treatment of Xenopus oocytes cleaved and inactivated cell surface XGPR3, which enhanced steroid-triggered oocyte maturation and activation of MAPK. In addition, human chorionic gonadotropin-treatment of follicle-enclosed oocytes triggered metalloproteinase-mediated cleavage of XGPR3 at the oocyte cell surface. Together, these results suggest that GPR3 moderates the oocyte response to maturation-promoting signals, and that gonadotropin-mediated activation of metalloproteinases may play a partial role in sensitizing oocytes for maturation by inactivating constitutive GPR3 signaling.
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PMID:The Xenopus laevis isoform of G protein-coupled receptor 3 (GPR3) is a constitutively active cell surface receptor that participates in maintaining meiotic arrest in X. laevis oocytes. 1851 95

Although studies suggest that the low competence of oocytes from prepubertal animals is due to their insufficient cytoplasmic maturation and that FSH improves oocyte maturation possibly by retarding meiotic progression and allowing more time for cytoplasmic maturation, the mechanisms by which puberty and gonadotropins regulate meiotic progression require additional detailed studies. For the first time, we observed that while meiotic progression was significantly slower, the maturation-promoting factor (MPF) activity of oocytes was significantly higher in prepubertal than in adult mice. To resolve this contradiction, we specified the molecules regulating the MPF activity and their localization during oocyte maturation in prepubertal and adult mice primed with or without gonadotropins. Our tests using corresponding enzyme regulators suggested that while activities of protein kinase A were unaffected, the activity of adenylate cyclase (ADCY) and phosphodiesterase increased while cell division cycle 2 homolog A (CDC2A) decreased significantly after puberty. While most of the adult oocytes had CDC2A protein concentrated in the germinal vesicle (GV) region, the majority of prepubertal oocytes showed no nuclear concentration of CDC2A. Maximally priming mice with equine chorionic gonadotropin brought the above parameters of prepubertal oocytes close to those in adult oocytes. Together, the results suggest that puberty and gonadotropin control oocyte meiotic progression mainly by regulating the ADCY activity and the concentration of the activated MPF toward the GV region.
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PMID:Effects of puberty and gonadotropins on the molecular events controlling meiotic resumption of mouse oocytes. 2038 81

Sildenafil citrate (Viagra), a cGMP-selective phosphodiesterase (PDE) inhibitor, is widely used to treat erectile dysfunction and pulmonary arterial hypertension. In contrast to its well established action on erectile dysfunction, little is known on the action of sildenafil on cGMP/cAMP signaling and testicular steroidogenesis. This study was designed to assess the effects of prolonged sildenafil treatment on NO synthase-dependent signaling and steroidogenic function of rat Leydig cells. Male adult rats were treated with Viagra (1.25 mg/kg body wt) daily for 30 days. In our studies, serum testosterone and ex vivo testosterone production significantly increased in sildenafil-treated animals. Human chorionic gonadotropin-stimulated testosterone production and cAMP accumulation were also significantly higher in Leydig cells obtained from sildenafil-treated rats. The expression of soluble guanylyl cyclase (GUCY1) subunits (Gucy1a1, Gucy1b1) significantly increased; cAMP-specific Pde4a, cGMP-specific Pde6c, and dual Pde1c and Nos2 were inhibited and expression of Nos3, protein kinase G1 (Pkg1), and Pde5 remained unchanged. Treatment of purified Leydig cells with NO donor caused a dose-dependent increase in both testosterone and cGMP production. Testosterone and cGMP production was significantly higher in Leydig cells obtained from sildenafil-treated animals. The stimulatory effect of NO donor was significantly enhanced by saturating concentrations of hCG in both Leydig cells obtained from control and sildenafil-treated animals. Occurrence of mature steroidogenic acute regulatory protein also increased in sildenafil treated animals in accord with increased cAMP and cGMP production. In summary, inhibition of PDE activity during prolonged sildenafil treatment increased serum testosterone level and Leydig cells' steroidogenic capacity by coordinated stimulatory action on cAMP and cGMP signaling pathway.
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PMID:Sildenafil treatment in vivo stimulates Leydig cell steroidogenesis via the cAMP/cGMP signaling pathway. 2066 85

In grass carp, luteinizing hormone (LH) can act locally within the pituitary to regulate growth hormone expression. To test if LH receptor (LHR) expression in the carp pituitary can also serve as a target of modulation for LH actions, grass carp LHR was cloned and characterized by functional expression. In carp pituitary cells, LHR mRNA (lhr) level could be reduced by LH or human chorionic gonadotropin (hCG) but up-regulated by dopamine treatment. Dopamine-induced lhr expression occurred mainly in carp somatotrophs via the cAMP/PKA pathway coupled to pituitary D1 receptors. This stimulatory effect could be blocked by LHR activation by hCG, presumably through phosphodiesterase III activation. These findings provide evidence that lhr expression in the carp pituitary is under the differential control of LH and dopamine via modification of cAMP-dependent signaling mechanisms, which may play a role in regulating somatotroph responsiveness to the paracrine action of LH in carp species.
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PMID:Gene expression of luteinizing hormone receptor in carp somatotrophs differentially regulated by local action of gonadotropin and dopamine D1 receptor activation. 2360 2


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