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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of cAMP in the control of follicular steroidogenesis of amago salmon (Oncorhynchus rhodurus) was studied using in vitro incubation of isolated thecal and granulosa layers. Particular attention was paid to the role of cAMP in the shift in the steroidogenic responses of follicle layers to gonadotropin (partially purified chum salmon gonadotropin, SGA) during oogenesis. First, the effects of SGA and forskolin, an activator of adenylate cyclase, on intratissue accumulation of cAMP were determined using isolated thecal and granulosa layers from various stages of development. Regardless of the stage of development, SGA and forskolin stimulated cAMP formation in both layers within 1 hr of incubation. Second, the effects of SGA, forskolin, dibutyryl cAMP, and inhibitors of phosphodiesterase on testosterone and 17 alpha-hydroxyprogesterone production by thecal layers and on the activities of aromatase and 20 beta-hydroxysteroid dehydrogenase in granulosa layers from follicles of various developmental stages were investigated. All steroidogenic actions of SGA were mimicked by those agents known to raise the cellular level of cAMP. These results provide evidence that the steroidogenic actions of gonadotropin in both thecal and granulosa layers depend on increased intracellular cAMP, and they further suggest that a change in cellular events at a step(s) subsequent to cAMP production is involved in regulating the shift in the steroidogenic responses of follicle layers to gonadotropin.
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PMID:Involvement of 3',5'-cyclic adenosine monophosphate in the control of follicular steroidogenesis of amago salmon (Oncorhynchus rhodurus). 284 8

Using the isolated perfused rabbit and rat ovaries as experimental models, we have studied various biochemical aspects of the ovulatory process. In rabbits, ovulations were induced by injecting hCG prior to the perfusion or by adding LH directly to the medium. In PMSG-treated rats, ovulations were induced by adding LH to the perfusion system. Steroids and other metabolites were analyzed in the perfusate and in follicular fluid. Steroid levels in follicular fluid were high early in the preovulatory development, but declined to very low levels 4 hours after LH stimulation. Levels of prostaglandins E and F rose as ovulation approached. In both perfusion models, indomethacin blocked ovulation without affecting steroid release or oocyte maturation. In the rabbit, PGF2 alpha reversed the indomethacin-induced inhibition and was able to induce follicular rupture by itself. Manipulations of the follicular fluid content of progesterone and estradiol to supraphysiological levels did not affect follicular rupture or oocyte maturation in the rabbit model. When the initial increase in LH-induced steroidogenesis was blocked by a 3 beta-ol-dehydrogenase inhibitor, ovulation was not affected. In rats, inhibition of estradiol production by an aromatase blocker did not affect the ovulatory process. When the endogenous formation of cyclic AMP is increased by pretreatment with a phosphodiesterase inhibitor, the LH-induced ovulation frequency increases in rabbits. Furthermore, forskolin, which increased the adenylate cyclase activity, stimulated steroidogenesis and induced follicular rupture. Recent experiments in the rat indicate that cyclic AMP acts on the ovulatory process via an effect on prostaglandin synthesis.
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PMID:Studies on the mechanism of ovulation using the model of the isolated ovary. 284 38

Sertoli cell-enriched cultures derived from 19-day old rats were exposed to FSH, L-isoproterenol, glucagon and dbcAMP for 24 up to 96 h. The influence of primary stimulation with these agonists on the response of the cells to subsequent stimulation with the homologous or heterologous agonists was investigated. Particular attention was paid to the response of the aromatase system defined as the ability of the cells to convert testosterone into 17 beta-estradiol. The responsiveness of this system was compared with the responsiveness of two other systems: adenylate cyclase and phosphodiesterase. It could be demonstrated that preincubation with the mentioned agonists results in a decreased responsiveness (maximal response) and a decreased sensitivity (ED50) upon re-stimulation with the homologous agonists. Preincubation with FSH also provokes partial desensitization for glucagon and L-isoproterenol. This heterologous desensitization can be mimicked by dbcAMP. The mentioned desensitization reactions are accompanied by a marked decrease in the accumulation of cAMP in the medium. Whereas desensitization of the adenylate cyclase occurs rapidly, desensitization of the aromatase response requires protracted stimulation for 3-4 days. In contrast with the adenylate cyclase and the aromatase system, the responsiveness of phosphodiesterase to FSH, L-isoproterenol, glucagon and dbcAMP is not affected by repeated stimulation for 96 h. It is concluded that hormonal desensitization affects both early (cAMP) and late (aromatase) responses of the Sertoli cell. However, some responses, such as phosphodiesterase activity seem to escape the desensitization process.
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PMID:Desensitization of Sertoli cell-enriched cultures by FSH, L-isoproterenol and glucagon. Influence on subsequent stimulation of 17 beta-estradiol production. 301 70

Male Wistar-Furth rats bearing the transplantable LTW(m) Leydig cell tumor have elevated serum estradiol (E2) concentrations. We measured the ability of these tumors to aromatize testosterone (T) to E2 by two methods. First, tumor minces were incubated with [7-3H]T, and the resultant [3H]E2 and [3H]estrone were purified and measured. In addition, tumor cell cultures were incubated with [1 beta-3H]T, and the resultant [3H]H2O was determined as a measure of aromatization. Tumor minces aromatized more actively than normal rat testicular tissue (3.30 +/- 0.15% of the T added was converted to E2 by the tumor vs. 0.30 +/- 0.25% by normal testis). Most of the aromatizing actitivity was localized to the microsomes. Using cell cultures the maximum velocity was 6.1 pmol/h X 5 X 10(5) cells, and the Km was 98 nM. In neither minces nor cell cultures were we able to show stimulation of aromatization with hCG, (Bu)2cAMP, or phorbol esters, although we could show stimulation by these agents in normal testicular cells. We were unable to inhibit the aromatase activity with human beta-endorphin or stimulate it with naloxone. However, we were able to inhibit the aromatase activity with 4-hydroxy-4-androstene-3,17-dione. We conclude that the LTW(m) rat Leydig cell tumor has an active autonomous aromatase system that is not responsive to compounds affecting the adenylate cyclase-cAMP system. It can be inhibited by 4-hydroxy-4-androstene-3,17-dione, a competitive-suicide inhibitor of the aromatase enzyme(s).
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PMID:Aromatase activity in a rat Leydig cell tumor. 303 Jul 2

Adult rat Leydig cell aromatase activity is stimulated 2.5 fold by LH or dbcAMP. Spent media prepared from seminiferous tubules or Sertoli cells of immature rats depress both the basal and the LH stimulated estradiol syntheses (25 and 20% decreases, respectively). These inhibitory effects are further enhanced when FSH is added to the culture medium of seminiferous tubules or Sertoli cells. Rat serum as well as culture media from other cell lines are ineffective while seminiferous tubule media from other immature animals (mouse, guinea-pig, calf) inhibit the aromatase activity. This Sertoli cell factor is a heat stable protein (molecular weight greater than 10 kDa), different from the LHRH-like Sertoli cell compound, which acts on the aromatase activity at a step beyond the adenylate cyclase.
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PMID:Spent media from immature seminiferous tubules and Sertoli cells inhibit adult rat Leydig cell aromatase activity. 303 Sep 13

The effects of FSH to increase the activity of aromatase, as well as the synthesis of the components of the aromatase enzyme complex, have been studied in human ovarian granulosa cells obtained from women undergoing oocyte retrieval. FSH increased aromatase activity, as well as the synthesis of aromatase cytochrome P-450 (P-450AROM) in a time-dependent fashion, whereas in the absence of FSH, both activity and synthesis declined with duration of culture. The effect of FSH was mimicked by forskolin, an activator of adenylate cyclase. FSH also increased the synthesis of NADPH-cytochrome P-450 reductase, but to a relatively modest extent. The levels of hybridizable mRNA species encoding cytochrome P-450AROM of lengths 3.0, 2.4, and 1.6 kilobases were also increased with FSH treatment. It is concluded that the regulation of aromatase activity by FSH in human granulosa cells is mediated primarily by changes in the synthesis of cytochrome P-450AROM, that this action of FSH is mediated by cAMP, and that the changes in cytochrome P-450AROM synthesis are the consequences of changes in the levels of mRNA encoding this enzyme.
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PMID:Regulation by follicle-stimulating hormone of the synthesis of aromatase cytochrome P-450 in human granulosa cells. 315 62

Adipose tissue is the major site of estrogen formation in postmenopausal women. We have previously reported (Simpson, E.R., Ackerman, G.E., Smith, M.E. and Mendelson, C.R. (1981) Proc. Natl. Acad. Sci. (U.S.A.) 78, 5690-5694; Mendelson, C.R., Cleland, W.H., Smith, M.E. and Simpson, E.R. (1982) Endocrinology 111, 1077-1085) that aromatase activity of human adipose stromal cells in culture is stimulated by glucocorticoids and by dibutyryl cyclic AMP (Bt2-cAMP). In order to establish which physiological factors might stimulate aromatase activity of these cells by activation of adenylate cyclase, we have investigated the roles of adrenocorticotropin (ACTH) and isoproterenol to increase cyclic AMP levels and stimulate the aromatization of androstenedione. In the presence of methylisobutylxanthine (MIX), ACTH stimulated cyclic AMP formation and aromatase activity in a time- and concentration-dependent manner. The concentration of ACTH required for half-maximal stimulation was approximately 10(-8) M. Isoproterenol, in the presence of MIX, stimulated cyclic AMP formation in a time- and concentration-dependent fashion, and also stimulated aromatase activity. These effects of isoproterenol appeared to be mediated by binding of the agonist to a population of beta-adrenergic receptors. On the basis of these and our previous studies, we suggest that ACTH may play an important role in stimulating estrogen formation by human adipose tissue, both directly, and by stimulating the adrenal cortex to produce both substrate, androstenedione, and inducing agent, namely cortisol.
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PMID:Regulation of aromatase activity of cultured adipose stromal cells by catecholamines and adrenocorticotropin. 620 18

The purpose of this investigation is to examine the mechanism by which progestins inhibit FSH-induced estrogen (E) production by cultured rat ovary granulosa cells. We have demonstrated that the highly potent synthetic progestin, R5020, is able to inhibit the induction of granulosa cell aromatase activity by cholera toxin, prostaglandin E2, dibutyryl cAMP or oFSH. Since the induction of E synthesis by these compounds is mediated through activation of adenylate cyclase and increased cellular cAMP production, these observations indicate that the progestin inhibitory effect is a post-cAMP event. In addition, we have demonstrated that R5020 does not inhibit FSH-stimulated granulosa cell cAMP production. The involvement of the granulosa cell progesterone (P) receptor as a mediator of this post-cAMP progestin effect is suggested by the relative abilities of various progestins to both bind the P receptor and to block the induction of granulosa cell aromatase activity by dibutyryl cAMP. While the precise mechanism of progestin action remains unclear, the kinetic analysis of aromatase enzyme activity demonstrates that progestins are not acting as competitive inhibitors of granulosa cell aromatase. Since E is necessary for follicular development, our in vitro data are consistent with the hypothesis that P is a factor which can inhibit FSH-induced follicular growth and development in the rat ovary.
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PMID:Progestins inhibit FSH-stimulated granulosa estrogen production at a post-cAMP site. 626 May 62

Direct inhibitory effects of LHRH and an LHRH agonist (ICI-118630) on FSH-controlled steroidogenic processes in ovarian granulosa cells were characterized in vitro. Over a 2-day culture period in the presence of testosterone (10(-7) M), FSH (3-3 000 ng/ml) caused dose-dependent increases in the aromatase activity of granulosa cells isolated from oestrogen-pretreated immature rats. Progestogen biosynthesis was stimulated in a similar manner. The presence of LHRH (10(-9) - 10(-7) M) in the culture medium inhibited these responses by right-shifting the dose-response curves. Thus the net effect was one of reduced sensitivity to FSH. ICI-118630 was approximately 10 times more effective than LHRH as an inhibitor of aromatase induction and progestogen biosynthesis in response to FSH. Over a 1-h incubation at concentrations up to 10(-7) M, neither decapeptide had a consistent inhibitory effect on FSH-stimulated granulosa cell cAMP formation either in the presence or absence of 1-methyl-3-isobutyl-xanthine (MIX); but during the 2-day culture, ICI-118630 and occasionally LHRH significantly inhibited aromatase induction by cholera toxin and 2 different cAMP analogues. Over the same range of concentrations, each peptide progressively inhibited the stimulatory effect of MIX on FSH-induced aromatase activity and progestogen biosynthesis. Thus LHRH/ICI-118630 can directly modulate FSH-controlled granulosa cell steroidogenesis in vitro via effects on one or more biochemical loci distal to the FSH-receptor coupled adenylate cyclase system. These experiments have implications for the role of a putative LHRH-like ovarian substance(s) in the local co-ordination of follicular development and function.
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PMID:Modulation of FSH-controlled steroidogenesis in rat granulosa cells: direct in-vitro effects of LHRH and ICI-118630. 626 72

Dicyclohexane derivatives are known to inhibit testosterone binding to rat androgen-binding protein (ABP) a secretory product of Sertoli cells. In this paper we show that these compounds also inhibit the aromatization of testosterone by Sertoli cells in response to cyclic AMP and to hormones that act via this nucleotide. The inhibitory activity of the nonsteroidal androgen analogues is dose-dependent and roughly parallels their ability to interfere with the aromatase activity in human placental microsomes and their affinity for ABP. Diethylstilbestrol and mesohexestrol--two nonsteroidal estrogens which resemble the dicyclohexane derivatives--also inhibit aromatase activity in Sertoli cells and placental microsomes. The effects of the synthetic estrogens on Sertoli cells, however, are less specific. Unlike the dicyclohexane derivatives they also block hormone induced activation of the adenylate cyclase. We conclude that dicyclohexane derivatives are representative of a novel series of inhibitors of aromatase activity.
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PMID:Dicyclohexane derivatives that bind to androgen-binding protein (ABP) also inhibit hormone stimulated aromatase activity in rat Sertoli cells. 630 96


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