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

---

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

The sequenc of biochemical events associated with the action of follicle-stimulating hormone (FSH) in the testis has been investigated using a Sertoli cell-enriched testis model system. The Sertoli cell-encriched testis, created by irradiation of male rats in utero, is devoid of germinal elements but contains a normal complement of supportive Sertoli cells. Comparison of the Sertoli cell-enriched testis with normal testis, demonstrates that the two types of testes contain equal numbers of FSH specific receptors, judged by the binding of labeled hormone. In addition, FSH over a concentration range from 6 X 10(-11) to 6 X 10(-9)M will stimulate the production of adenosine 3',5' monophosphate (cAMP) in the Sertoli cell-enriched testis in a manner indistinguishable from that of the normal testis. Incubation of Sertoli cell enriched testis also results in the activation of soluble cAMP-dependent protein kinase. This response to FSH is dependent upon the age of the animal and disappears at about 32 days of age. While sensitivity to the hormone can still be detected in mature Sertoli cell-enriched animals by the addition of the phosphodiesterase inhibitor 1-methyl-3-isobutyl-xanthine, no detectable increase in phosphodiesterase activity is apparent after 30 days of age. Injection of FSH into Sertoli cell-enriched animals results in an increase in total testicular protein synthesis as well as in the production of the Sertoli cell-specific protein, androgen-binding protein within 30 minutes. Furthermore, while hypophysectomy of Sertoli cell-enriched animals result in a decline of the testicular concentration of androgen-binding protein, the injection of FSH will stimulate and maintain the levels of androgen-binding protein in such animals. These results demonstrate that the Sertoli cell-enriched testis is capable of carrying out the sequence of biochemical events previously described for FSH in the normal testis and therefore, suggest that the Sertoli cell is the primary target cell for FSH action.
...
PMID:Biochemical actions of follice-stimulating hormone in the sertoli cell of the rat testis. 17 98

The regulation by FSH (follitropin; follicle-stimulating hormone) of FSH receptor mRNA and protein (FSH binding) was studied using cultured Sertoli cells isolated from 21-day-old rats. FSH induced a dose-dependent and almost complete down-regulation of receptor mRNA at 4 h after addition of the hormone. At subsequent time points (16 h and later) the FSH receptor mRNA levels had returned close to control values. The effect of FSH was mimicked by dibutyryl cyclic AMP (dbcAMP) and forskolin, and the phosphodiesterase inhibitor methyl-isobutylxanthine (MIX) prolonged the FSH action. These findings indicate that the effect of FSH on its receptor mRNA was mediated by cAMP. A down-regulatory effect of FSH and dbcAMP on FSH receptor mRNA was also observed in the presence of the protein synthesis inhibitor cycloheximide, suggesting a direct effect of FSH/dbcAMP on the expression of the FSH receptor gene. Transcriptional run-on experiments revealed that FSH did not inhibit initiation of the FSH receptor gene; hence a post-transcriptional mechanism is involved. Binding of 125I-FSH to the cultured Sertoli cells was rapidly (4 h) decreased when the cells were incubated with FSH or FSH in combination with MIX. This effect can be explained by ligand-induced receptor sequestration. In contrast, incubation of Sertoli cells with dbcAMP had no effect on binding of 125I-FSH after 4 h, but resulted in a 60% loss of FSH binding sites after 24 h, probably caused by decreased mRNA expression. In conclusion, FSH receptor down-regulation in Sertoli cells is effected not only by the well-documented ligand-induced loss of receptors from the plasma membrane, but also involves a cAMP-mediated decrease of FSH receptor mRNA through a post-transcriptional mechanism.
...
PMID:Follitropin receptor down-regulation involves a cAMP-dependent post-transcriptional decrease of receptor mRNA expression. 172 86

The present study was carried out to examine the role of protein synthesis in mouse oocyte maturation in vitro. In the first part of this study, the effects of cycloheximide (CX) were tested on spontaneous meiotic maturation when oocytes were cultured in inhibitor-free medium. CX reversibly suppressed maturation of oocytes as long as maturation was either initially prevented by the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), or delayed by follicle-stimulating hormone (FSH). In the second part of this study, the actions of protein synthesis inhibitors were tested on hormone-induced maturation. CEO were maintained in meiotic arrest for 21-22 h with hypoxanthine, and germinal vesicle breakdown (GVB) was induced with follicle-stimulating hormone (FSH). Three different protein synthesis inhibitors [CX, emetine (EM), and puromycin (PUR)] each prevented the stimulatory action of FSH on GVB in a dose-dependent fashion. This was accompanied by a dose-dependent suppression of 3H-leucine incorporation by oocyte-cumulus cell complexes. The action of these inhibitors on FSH- and epidermal growth factor (EGF)-induced GVB was next compared. All three drugs lowered the frequency of GVB in the FSH-treated groups, below even that of the controls (drug + hypoxanthine); the drugs maintained meiotic arrest at the control frequencies in the EGF-treated groups. Puromycin aminonucleoside, an analog of PUR with no inhibitory action on protein synthesis, had no effect. The three inhibitors also suppressed the stimulatory action of FSH on oocyte maturation when meiotic arrest was maintained with the cAMP analog, dbcAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Protein synthesis inhibitors prevent both spontaneous and hormone-dependent maturation of isolated mouse oocytes. 212 75

Xenopus ovarian follicles consist of single large oocytes surrounded by a layer of small follicle cells that are coupled to the oocyte by gap junctions. Hyperpolarizing K+ currents can be detected in the oocytes of follicles stimulated with adenosine, isoproterenol, follicle-stimulating hormone (FSH), or microinjected adenosine 3',5'-cyclic monophosphate (cAMP). We show that cAMP accumulation can be detected in follicles incubated with the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), isoproterenol, or FSH, but only if forskolin and a phosphodiesterase inhibitor are also added. Treatment of follicles with collagenase has been reported to reduce, but usually not to eliminate, cAMP-activated K+ currents. In this study we show that collagenase treatment alone does not completely remove follicle cells or receptor-mediated cAMP accumulation measured in follicles. cAMP accumulation and cAMP-dependent K+ currents are both eliminated when the follicle cells are completely removed by a technique involving treatment of follicles with collagenase and hypertonic saline. Oocytes completely stripped of follicle cells fail to accumulate cAMP in response to receptor agonists and forskolin. Isolated follicle cells derived from single follicles (but without the oocyte present) accumulate cAMP in response to these drugs to an extent equivalent to the response seen in single intact follicles. Adenylyl cyclase-linked receptors of Xenopus follicles thus appear to be located exclusively on follicle cells. The data suggest that cAMP-dependent K+ currents, although measured in oocytes, may be generated in follicle cells which communicate with oocytes. Another possibility is that a high resting K+ conductance in follicle cells is communicated to oocytes via cAMP-sensitive gap junctions.
...
PMID:Xenopus oocyte K+ current. II. Adenylyl cyclase-linked receptors on follicle cells. 217 13

The intermediary role and relative importance of cAMP in follicle-stimulating hormone (FSH) hormonal action were reinvestigated at the level of the rat granulosa cell employing Rp-cAMPS, a novel antagonistic analog of cAMP. This approach may not only provide for direct documentation of cAMP dependence, but may also, by inference, highlight the potential relative importance of other putative intracellular second messenger systems. Initial cell-free validation studies indicated that Rp-cAMPS is capable of effectively competing with cAMP for binding to and activation of the regulatory subunit of the granulosa cell A-kinase holoenzyme. Subsequent whole-cell studies employed cultured rat granulosa cells, the cAMP-phosphodiesterase activity of which was suppressed with ZK62711. Basal progesterone accumulation was relatively low, remaining unaffected by treatment with a maximally effective dose of Rp-cAMPS by itself (10(-3) M). Whereas treatment with FSH (30 ng/ml) resulted in a substantial increase in progesterone accumulation, concurrent treatment with increasing concentrations (10(-6)-10(-3) M) or Rp-cAMPS brought about dose-dependent decrements in the FSH effect with a median effective dose of 1.8 +/- (SE) 0.4 x 10(-5) M and a maximal, but incomplete inhibitory effect of 70 +/- (SE) 6%. Higher concentrations of FSH (greater than or equal to 100 ng/ml) progressively diminished, but did not abolish the Rp-cAMPS blockade. Removal of Rp-cAMPS resulted in progressive resumption of FSH responsiveness suggesting reversibility of action. Significantly, Rp-cAMPS proved highly effective in blocking the action of its agonistic diastereomer Sp-cAMPS. However, Rp-cAMPS was unable to block the action of the lactogenic receptor agonist prolactin, the second messenger of which remains uncertain. Taken together, these findings provide additional direct support to the notion that cAMP may be an intracellular second messenger of FSH. However, to the extent that Rp-cAMPS is incapable of complete neutralization of FSH action, our findings further suggest that cAMP may play a central, albeit non-exclusive role in FSH-supported granulosa cell differentiation and that other putative second messenger systems may also be at play.
...
PMID:Blockade of granulosa cell differentiation by an antagonistic analog of adenosine 3',5'-cyclic monophosphate (cAMP): central but non-exclusive intermediary role of cAMP in follicle-stimulating hormone action. 217 13

Hypoxanthine and adenosine are present in preparations of mouse ovarian follicular fluid, and these purines maintain mouse oocytes in meiotic arrest in vitro (Eppig et al.: Biology of Reproduction 33:1041-1049. 1985). The first hypothesis tested in this study is that purines which maintain meiotic arrest act by maintaining meiosis-arresting levels of cyclic adenosine monophosphate (cAMP) in the oocyte. Oocyte-cumulus cell complexes were incubated in control medium (no added purines), or medium containing 0.75 mM adenosine, 4 mM hypoxanthine, or both for 3 hr and the percentage of the oocytes that underwent germinal vesicle breakdown (GVB) and the cAMP content of the intact complexes and the oocytes were determined. Adenosine alone had little inhibitory effect on GVB at this time point but sustained higher levels of cAMP in the oocytes. Hypoxanthine maintained 80% of cumulus cell-enclosed oocytes in meiotic arrest and also sustained higher cAMP levels in the oocytes. The addition of adenosine to hypoxanthine-containing medium increased the percentage of oocytes maintained in meiotic arrest, and increased the amount of cAMP in the oocytes above that maintained by either hypoxanthine or adenosine alone. Neither hypoxanthine, adenosine, nor hypoxanthine plus adenosine altered the cAMP content of intact complexes when assayed after 3 hr culture. Microinjection of an inhibitor of the catalytic subunit of cAMP-dependent protein kinase induced GVB in denuded oocytes cultured in medium containing hypoxanthine. This purine, therefore, maintained meiotic arrest by sustaining elevated cAMP levels within the oocytes. The second hypothesis tested in this study is that purines maintain meiosis-arresting levels of cAMP, at least in part, by inhibiting cAMP phosphodiesterase activity. In descending order of potency, 3-isobutyl-1-methylxanthine (IBMX), guanosine, hypoxanthine, adenosine, and xanthosine inhibited cAMP phosphodiesterase in oocyte lysates. Moreover, like the potent phosphodiesterase inhibitor IBMX, hypoxanthine augmented the meiotic arrest and cAMP accumulation mediated by follicle-stimulating hormone (FSH) in intact complexes. Therefore, inhibition of oocyte phosphodiesterase appears to be one mechanism by which the purines could maintain meiosis-arresting levels of cAMP.
...
PMID:Maintenance of meiotic arrest in mouse oocytes by purines: modulation of cAMP levels and cAMP phosphodiesterase activity. 247 69

High doses of phthalate esters in vivo cause testicular lesions. One initial target for these effects is the sustentacular Sertoli cell. Sertoli cells are unique in that they have surface membrane receptors for follicle-stimulating hormone (FSH), which couple to adenylate cyclase. As a means of investigating why phthalates appear specific for Sertoli cells, we evaluated possible effects of an active monoester [mono(2-ethylhexyl) phthalate, MEHP] on the ability of FSH to elevate intracellular levels of cAMP. MEHP reduced FSH-induced elevation of cAMP levels by approximately 40%. This inhibition by MEHP required a lag period of 6 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that MEHP does not compete with FSH for binding to its receptor. The MEHP inhibition was not affected by incubation in the presence of methylisobutylxanthine, a phosphodiesterase inhibitor, suggesting that MEHP does not stimulate the breakdown of cAMP. The MEHP-induced inhibition is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin suggesting that MEHP action is independent of the inhibitory adenylate cyclase pathway. Further experiments will be necessary to define the specific mechanism of action of phthalates on Sertoli cells; however, these experiments do describe a specific site of action of MEHP in vitro which may be related to the in vivo testicular toxicity of phthalate esters.
...
PMID:Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. 253 9

To elucidate the mechanisms by which hormones regulate cAMP phosphodiesterases (PDEs), a group of cDNA clones that had been isolated from a rat Sertoli cell library were characterized. These cDNAs are derived from a single gene (ratPDE3). The deduced amino acid sequence of the ratPDE3 cDNA corresponds to a 66,200-Da protein homologous to other testicular PDEs, to the Drosophila melanogaster dunce-encoded cAMP PDE, and to bovine and yeast PDEs. Expression of ratPDE3 in eukaryotic and prokaryotic cells leads to the appearance of a cAMP PDE with properties identical to the cAMP PDE purified from Sertoli cells. Although of different size, transcripts corresponding to ratPDE3 were present in all organs studied. In the immature Sertoli cell in culture, the level of mRNA transcripts of ratPDE3 was increased more than 100-fold by follicle-stimulating hormone or N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate treatment. Stimulation of ratPDE3 mRNA by N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate was also observed in a C6 glioma cell line. These data demonstrate that cAMP regulates the expression of one of its own degrading enzymes by an intracellular feedback mechanism that involves changes in mRNA levels.
...
PMID:The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. 255 3

In this study we examined the effects of A23187 (a calcium ionophore) and 12-O-tetradecanoyl phorbol-13-acetate, a known activator of protein kinase C, on progesterone production. Granulosa cells obtained from pregnant mare serum gonadotropin-primed rats were maintained in primary culture. Treatment with follicle-stimulating hormone (0.5 microgram/ml), 8-bromo-adenosine-3',5'-cyclic monophosphate (2 mmol/L), or cholera toxin (0.1 microgram/ml) for 5 hours or 24 hours markedly stimulated progesterone production. The concomitant presence of A23187 attenuated the elevated levels of progesterone induced by follicle-stimulating hormone, 8-bromo-adenosine-3',5'-cyclic monophosphate, or cholera toxin, with or without the presence of a phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (0.2 mmol/L). Likewise, treatment of the cells with 12-O-tetradecanoyl phorbol-13-acetate suppressed follicle-stimulating hormone-induced progesterone production, whether or not 1-methyl-3-isobutylxanthine was present in the cultures. The effect of 12-O-tetradecanoyl phorbol-13-acetate was not mimicked by phorbol-13-monoacetate or 4 alpha-phorbol-12, 13-didecanoate. These results indicate that both A23187 and 12-O-tetradecanoyl phorbol-13-acetate inhibit follicle-stimulating hormone-induced progesterone production, in part at a step or steps beyond adenosine-3',5'-cyclic monophosphate generation and degradation. They further support a role of calcium and protein kinase C in the intraovarian action of luteinizing hormone-releasing hormone.
...
PMID:Inhibition of follicle-stimulating hormone- and adenosine-3',5'-cyclic monophosphate-induced progesterone production by calcium and protein kinase C in the rat ovary. 282 29

The efficacy of follicle-stimulating hormone (FSH), epidermal growth factor (EGF), and dibutyryl cGMP (dbcGMP) as inducers of germinal vesicle breakdown (GVBD) in cumulus cell-enclosed mouse oocytes was examined when meiotic arrest was maintained in vitro with purines, dibutyryl cAMP (dbcAMP), or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). When FSH was added to hypoxanthine (HX)-containing medium, the effect on oocyte maturation was at first inhibitory and later stimulatory. EGF stimulated GVBD at all time points tested. FSH and EGF also induced GVBD when oocytes were arrested with dbcAMP, IBMX, or guanosine. Dibutyryl cGMP stimulated GVBD when meiotic arrest was maintained with HX, but not when oocytes were meiotically arrested with guanosine, and was inhibitory in dbcAMP-supplemented medium. FSH and dbcGMP produced a transient delay of oocyte maturation in control medium, but the FSH effect was much more pronounced. EGF had no effect on maturation kinetics. The actions of FSH and EGF required the presence of cumulus cells. Both agents significantly stimulated cAMP production in oocyte-cumulus cell complexes. A brief exposure of complexes to a high concentration of dbcAMP induced GVBD, suggesting that FSH and EGF may act via a cAMP-dependent process. The frequency of FSH- and EGF-induced GVBD in cumulus cell-enclosed oocytes was significantly higher than the frequency of GVBD when oocytes were cultured while denuded of cumulus cells. of maturation is apparently not mediated solely by oocyte-cumulus cell uncoupling and termination of the transfer of an inhibitory meiotic signal from cumulus cells to the oocyte. The data suggest the generation of a positive signal within cumulus cells in response to hormone treatment that acts upon the oocyte to stimulate GVBD in the continued presence of inhibitory factors.
...
PMID:Induction of maturation in cumulus cell-enclosed mouse oocytes by follicle-stimulating hormone and epidermal growth factor: evidence for a positive stimulus of somatic cell origin. 283 12


1 2 3 4 Next >>

---