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)

In continuing studies on cyclic nucleotide involvement in the regulation of gonadotropin release, we have measured the cyclic nucleotide content and rate of LH and FSH release during stimulation by LHRH of dispersed overnight cultured cells from the pituitaries of adult female rats. The minimal effective concentration of LHRH was 0.1 nM and half maximal stimulation of gonadotropin release was observed in the presence of 1.0 nM LHRH. Significant release of both LH and FSH was detectable after only 10 min in the presence of 5 nM LHRH. The presence of fetal calf serum (FCS) in the overnight culture medium increased basal cGMP levels significantly, whereas horse serum (HS) had no effect, therefore all experiments were conducted on cells cultured in the presence of HS. Treatment of the cultured cells with the phosphodiesterase inhibitors theophylline (TH) or isobutyl-methyl-xanthine (MIX) revealed a preferential stimulatory effect of TH on basal cAMP levels and of MIX on cGMP levels. Throughout these experiments, LHRH had no effect on cAMP levels. In the presence of MIX, concentrations of the releasing hormone as low as 1 nM induced a significant rise in the level of cGMP whereas in its absence, cGMP levels appeared to be unchanged by LHRH. The increase was detectable after 10 min of incubation. MIX alone slightly increased LH and FSH release and significantly potentiated the response of the cells to increasing doses of LHRH up to, but not beyond, 10 nM. The data support the possibility that cGMP may be involved in the mechanism of action of LHRH.
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PMID:A possible role for cyclic GMP in mediating the effect of luteinizing hormone releasing hormone on gonadotropin release in dispersed pituitary cells of the female rat. 8 42

A series of studies was conducted to evaluate the ability of several second messengers/second messenger systems to stimulate LH secretion from dispersed chicken pituitary cells. [Gln8]-LHRH-(cLHRH) stimulated LH secretion in a dose-dependent fashion; this effect was potentiated in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, and was mimicked by the cAMP analog, 8-bromo-cAMP. These data indicate that the production of cAMP in response to cLHRH can stimulate LH secretion, but do not necessarily provide evidence that such production is prerequisite. The tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), and diacylglycerol analogs, 1-oleoyl-2-acetylglycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG), also stimulated LH release; however, only PMA (and not cLHRH or DOG) promoted an accumulation of cAMP. The putative protein kinase C inhibitor, staurosporine, completely blocked LH release stimulated by PMA, but failed to block cLHRH-induced LH secretion. Such results indicate that protein kinase C activation can promote LH secretion, but also suggest that additional second messengers may exist to fully mediate the effects of cLHRH. Both the calcium ionophore, A23187, and the intracellular calcium mobilizing agent, thapsigargin, caused a dose-dependent increase in LH secretion; furthermore, thapsigargin augmented the stimulatory effects of PMA. These data are consistent with a role for calcium in the regulation of LH release, and indicate that the mobilization of intracellular calcium alone can affect such an action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Second messenger pathways mediating chicken luteinizing hormone secretion from dispersed pituitary cells. 171 94

A role for cAMP in the process of LHRH release was suggested several years ago, but only recently has the validity of this notion come under close scrutiny. In the present experiments we have used three probes, which stimulate adenylate cyclase activity via different mechanisms, to determine whether an increase in endogenous cAMP results in LHRH release from the hypothalamus of prepubertal female rats. Median eminences from juvenile, 28-day-old animals were incubated in vitro with either forskolin (F), cholera toxin (CT), or pertussis toxin (PT). All three substances enhanced LHRH release. The estimated ED50 values were 28.7 microM and 20.0 ng/ml, for F and PT, respectively. The effect of CT appeared biphasic and thus no ED50 could be calculated. None of these agents increased the release of prostaglandin E2 (PGE2), an obligatory component in the process of norepinephrine-induced LHRH secretion. Doses of PGE2 and F, which were maximally effective in stimulating LHRH release when administered separately, did not produce any further response when administered concomitantly, thus suggesting that PGE2 and F act along a common pathway. Blockade of phosphodiesterase activity with 1-methyl-3-isobutylxanthine increased LHRH secretion without enhancing PGE2 release, implying that cAMP metabolism was elevated in the median eminence nerve terminals in vitro. Addition of 1-methyl-3-isobutylxanthine augmented the LHRH response to CT and PT, but it did not increase further the already marked LHRH response to PGE2 or F. The results indicate that both an increase in adenylate cyclase activity and a decrease in phosphodiesterase activity lead to LHRH release from the median eminence. They also suggest that, upon proper (neurotransmitter?) stimulation, cAMP production increases subsequent to the activation in PGE2 synthesis, which itself causes LHRH release. Furthermore, the capacity of PT to induce LHRH release suggests the involvement of an inhibitory guanine nucleotide-binding regulatory protein in transducing inhibitory inputs impinging on LHRH-secreting neurons.
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PMID:Stimulation of cyclic adenosine 3',5'-monophosphate production enhances hypothalamic luteinizing hormone-releasing hormone release without increasing prostaglandin E2 synthesis: studies in prepubertal female rats. 241 Feb 36

Characterization of specific vasopressin binding sites was investigated in purified mouse Leydig cells using tritiated arginine-vasopressin. Binding of radioligand was saturable, time- and temperature-dependent and reversible. (3H)-AVP was found to bind to a single class of sites with high affinity (Kd = 2.20 +/- 0.18 nM) and low capacity (Bmax = 17.4 +/- 1.8 fmol/10(6) Leydig cells). Binding displacements with specific selective analogs of AVP indicated the presence of V1 subtype receptors on Leydig cells. The ability of AVP to displace (3H)-AVP binding was greater than LVP and oxytocin. The unrelated peptides, somatostatin and substance P, were less potent, while neurotensin and LHRH did not displace (3H)-AVP binding. The time-course effects of AVP-pretreatment on basal and hCG-stimulated testosterone and cAMP accumulations were studied in primary culture of Leydig cells. Basal testosterone accumulation was significantly increased by a 24 h AVP-pretreatment of Leydig cells (P less than 0.001). This effect was potentiated by the phosphodiesterase inhibitor (MIX) and was concomitantly accompanied by a slight but significant increase in cAMP accumulation (P less than 0.01). AVP-pretreatment of the cells for 72 h had no effect on basal testosterone accumulation, but exerted a marked inhibitory effect on the hCG-stimulated testosterone accumulation (P less than 0.001). This reduction of testosterone accumulation occurred even in the presence of MIX and was not accompanied by any significant change of cAMP levels. We conclude from these data that AVP is capable of modulating steroidogenesis in Leydig cells through specific and functionally V1 receptor subtype and postulate that this effect may be part of an intratesticular paracrine/autocrine control mechanism.
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PMID:Modulation of mouse Leydig cell steroidogenesis through a specific arginine-vasopressin receptor. 245 54

We examined basal and gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release and synthesis in response to drugs that raise intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels. Anterior pituitaries from ovariectomized rats were incubated with or without drugs in the presence of GnRH and [3H]glucosamine. Neither 8-bromo-cAMP (8-Br-cAMP) (10 mM), cholera toxin (10 micrograms/ml), nor phosphodiesterase inhibitors [theophylline, 2 and 8 mM; 3-isobutyl-1-methylxanthine (MIX), 0.2 mM] had any detectable effect on release of immunoreactive LH (IR-LH) when used alone. However, 8-Br-cAMP and the inhibitors potentiated (P less than 0.01) GnRH-induced release of IR-LH. Total radiolabeled LH in the system was elevated (P less than 0.01) by either GnRH, 8-Br-cAMP for cholera toxin, but reduced (P less than 0.01) by 8 mM theophylline and unaffected by MIX or 2 mM theophylline. 8-Br-cAMP did not alter the effect of GnRH on radiolabeled LH in the total system, whereas MIX and 2 mM theophylline reduced (P less than 0.05) it. These results suggest that 1) cAMP does not effect LH release directly, but may interact with GnRH to potentiate it, 2) GnRH and cAMP have a similar mode of action on LH glycosylation, and 3) phosphodiesterase inhibitors have additional actions that interfere with LH glycosylation.
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PMID:Effects of GnRH and drugs that affect cAMP levels on LH synthesis and release. 616 3

Short-term (4 h) incubation of collagenase-dispersed Leydig cells from adult rats in the presence of an LHRH agonist caused a 2-3-fold stimulation (P less than 0.001) of testosterone production. This effect was dose-dependent and as little as 5 x 10(-11) M LHRH agonist caused significant stimulation whilst maximal effects were achieved with 10(-9) M concentrations. Stimulation of steroidogenesis by LHRH agonist was prevented by addition of an antiserum specific for the peptide, but was exaggerated in the presence of the phosphodiesterase inhibitor MIX, suggesting the involvement of cyclic AMP in the response of the Leydig cells to the agonist. Native LHRH caused a similar degree of stimulation of testosterone secretion to LHRH agonist but concentrations 1000 times greater than those of the agonist were required to achieve this, a finding consistent with the known affinities of these 2 peptides for the Leydig cell LHRH-receptor. The addition of LHRH agonist also enhanced (P less than 0.001) testosterone secretion by adult rat Leydig cells in response to hCG or dibutyryl cyclic AMP, and this effect was still evident in the presence of maximally-stimulating concentrations of these factors. LHRH agonist also stimulated testosterone secretion by Leydig cells from immature rats, but this effect differed from that in the adult in being of smaller magnitude and being restricted to effects on basal secretion or secretion elicited by low concentrations of hCG. These results show for the first time (a) that LHRH and its agonists can exert effects on Leydig cell steroidogenesis during short-term incubation, and (b) that these effects are stimulatory, which contrasts with the inhibitory effects reported after long-term (2-3 days) exposure of Leydig cells to LHRH agonists in vivo and in vitro. The availability of this simple and rapid measure of a biological action of LHRH on the Leydig cell should enable its precise mode of action to be determined, and should throw light on the physiological role of endogenously produced testicular 'LHRH'.
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PMID:Stimulatory effect of LHRH and its agonists on Leydig cell steroidogenesis in vitro. 617 69

The effects of an LHRH agonist on LH- and forskolin-stimulated cyclic AMP and testosterone production have been investigated in purified rat Leydig cells in vitro. In agreement with previous results it was found that preincubation with LHRH agonist inhibited subsequent LH-stimulated cyclic AMP production. At least 2 h preincubation was required and this effect of the LHRH agonist was negated by the protein synthesis inhibitor cycloheximide and by the phosphodiesterase inhibitor methylisobutylxanthine (MIX). Forskolin-stimulated cyclic AMP production was not inhibited by the LHRH agonist. Forskolin increased testosterone production to the same levels attained by LH and preincubation with LHRH agonist increased both forskolin- and LH-stimulated testosterone production. The data obtained suggest that LHRH agonist increases the synthesis of an inactive form of phosphodiesterase (or associated protein) which is activated by LH via a mechanism not involving cyclic AMP.
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PMID:LHRH agonist decreases LH- but not forskolin-stimulated cyclic AMP levels in rat Leydig cells in vitro. 620 93

Effects of gonadotropin and LHRH on the cAMP levels, adenylate cyclase and cyclic nucleotide phosphodiesterase activities of the pineal, hypothalamus, pituitary, adrenal and ovary of the female pubertal rabbits were examined, and serum FSH, LH, estradiol and progesterone were measured. Gonadotropin and LHRH were injected intravenously five days, and 16 hours after the last administration, experiments were performed. The cAMP levels in the endocrine organs of the female pubertal rabbits were higher than adults. Gonadotropin and LHRH administration decreased the cAMP levels, i.e. draw to the levels of adults, in almost all endocrine organs. In pre-pubertal period (5-7 weeks of age), cAMP responses of hypothalamus and pituitary to gonadotropin or LHRH were significant, whereas responses of adrenal and ovary were slight and not significant. In early and mid-pubertal period (9-14 weeks of age), changes of the cAMP levels in the hypothalamus and pituitary were slight than pre-pubertal period, but in ovary, remarkable change of the cAMP levels were observed. The adenylate cyclase activities of all endocrine organs were not changed and the phosphodiesterase activities were increased by gonadotropin or LHRH administration. Serum FSH, LH estradiol and progesterone were increased with age. The most remarkable increases were occurred to the serum FSH level of pre-pubertal rabbits (7 weeks of age) after gonadotropin or LHRH administration, and serum progesterone of mid-pubertal rabbits (14 weeks of age) after gonadotropin administration.
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PMID:[Effects of gonadotropin and LHRH on the cAMP levels, adenylate cyclase and cyclic nucleotide phosphodiesterase activities in the endocrine organs of the female pubertal rabbits (author's transl)]. 627 82

The antigonadal effects of gonadotropin-releasing hormone in ovarian granulosa cells are due to attenuation of the adenosine 3',5'-monophosphate (cyclic AMP) response to follicle-stimulating hormone. Agonists of gonadotropin-releasing hormone progressively inhibit adenylate cyclase and stimulate phosphodiesterase activities in cultured granulosa cells, indicating that blockade of gonadotropin action is attributable to the combined effects of decreased production and increased degradation of cyclic AMP.
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PMID:Gonadotropin-releasing hormone: regulation of adenosine 3',5'-monophosphate in ovarian granulosa cells. 627 16

The mechanism of action of a gonadotropin releasing hormone (GnRH) agonistic analog ([D-Ala6]GnRH) on the rat ovary has been studied in comparison to similar effects of luteinizing hormone (LH). Stimulation of meiosis resumption in vitro in follicle-enclosed oocytes by both LH and [D-Ala6] GnRH, was blocked by elevated levels of cAMP as demonstrated when either dibutyryl cAMP or the phosphodiesterase inhibitor methylisobutylxanthine was present in the culture medium. In vivo, the prostaglandin synthase inhibitor indomethacin, which blocks LH-induced ovulation, also inhibited ovulation induced by the GnRH analog in hypophysectomized rats. On the other hand, the potent GnRH-antagonist [D-pGlu1, pClPhe2, D-Trp3,6] GnRH which blocked the stimulatory effect of the agonist on oocyte maturation and ovulation had no effect on LH action. It is concluded that while a GnRH-like peptide does not seem to mediate LH action on the ovarian follicles, both LH and GnRH agonist share some common mechanistic pathways at a post-receptor locus.
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PMID:A comparative study of the mechanism of action of luteinizing hormone and a gonadotropin releasing hormone analog on the ovary. 629 11


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