Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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.
 ...
PMID:Modulation of FSH-controlled steroidogenesis in rat granulosa cells: direct in-vitro effects of LHRH and ICI-118630. 626 72

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.
 ...
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 hallmark of the preovulatory follicles in the rat ovary appears to be the presence of receptors for both LH and FSH on follicular granulosa cells. We have tested the possibility that both gonadotropin receptors could share a common adenylate cyclase system utilising cell fusion techniques. Adenylate cyclase (and concomitant stimulation of progesterone synthesis) was inactivated in granulosa cells possessing both FSH and LH receptors by incubation of the cells with N-ethylmaleimide. This treatment did not affect hormone binding to the cells. Subsequent fusion, using polyethylene glycol, of the cyclase-inactivated cells with granulosa cells possessing FSH receptors only and an active cyclase restored LH stimulation of cAMP and progesterone production. These findings support the hypothesis that the LH and FSH receptors on granulosa cells of preovulatory follicles share a common adenylate cyclase system.
 ...
PMID:Granulosa cell fusion allows heterologous receptor stimulation of adenylate cyclase and progesterone accumulation. 627 52

Immature female rats were injected with a single dose (10 IU) of pregnant mare serum gonadotropin to induce growth and maturation of ovarian follicles. Using such ovaries as a model, we tested the effects of low molecular weight subfractions of charcoal-absorbed bovine follicular fluid (FF-c) on (a) radioiodinated human FSH (125I-hFSH) binding to ovarian homogenates, (b) ovine FSH-stimulated adenylate cyclase activity in granulosa cell homogenates and (c) cAMP production by intact granulosa cells. The follicular fluid was fractionated by ultrafiltration through membranes of differing pore-sized into molecular weight components of 1000-5000 (passing Amicon H1P-5 hollow fibers but retained by Amicon UM-2 membrane) and 500-1000 (passing Amicon UM-2 membrane but retained by Amicon Um-05 membrane). These low molecular weight fractions inhibited 125I-hFSH binding to ovarian receptors, FSH-stimulated cAMP production by rat granulosa cells and FSH-stimulated, as well as fluoride-ion-stimulated adenylate cyclase activity in granulosa cell homogenates. Inhibition of FSH-stimulated adenylate cyclase activity by the FF subfractions was non-competitive as determined by double reciprocal plot analysis. Our results suggest that modulation of FSH effects on granulosa cells may be mediated by low molecular weight constituents of follicular fluid.
 ...
PMID:Inhibition of FSH action on granulosa cells by low molecular weight components of follicular fluid. 627 60

The interaction of FSH with membrane receptors from rat and calf testis has been studied in some detail. The FSH receptor has been solubilized through use of the nonionic detergent Triton X-100 and highly purified by affinity chromatography on Affigel-10 coupled to ovine FSH. Hormone binding activity of the solubilized receptor has been preserved for extended periods through use of the structure-stabilizing agent glycerol. Other components of the FSH testes receptor system including the guanyl nucleotide binding protein and adenylate cyclase have been solubilized by nonionic detergents and also found to be stabilized by glycerol. FSH binding activity has been observed in testes cytosol and represents a putative class of receptors prepared from testes in the absence of detergent. The concentration of this buffer-soluble component decreased with age and increased concomitantly with loss of membrane receptors consequent to their down-regulation after administration of exogenous FSH. Phospholipids seem involved in the interaction of FSH with membrane-bound, detergent-solubilized, and buffer-soluble FSH binding activity. Phospholipids may maintain or stabilize a particular receptor conformation necessary for interaction with the hormone. A specific role for GTP seems indicated in regulation of FSH-stimulated adenylate cyclase activity in immature rat testis. Follitropin binding to testes receptor appears modulated by a variety of factors present in serum, testes extracts, follicular fluid, and seminal plasma, which are poorly understood at present. Inhibition of FSH binding by seminal plasma best-fit by a model proposing two hormone binding sites per receptor molecule, where binding to one site decreases the affinity of the other site for FSH. As a result of studies in this and other laboratories, the molecular endocrinology of FSH interaction with testis receptors is becoming increasingly understood.
 ...
PMID:Biochemical properties of the testicular follitropin-receptor system. 628 87

The regulation of ovarian gonadotropin-sensitive adenylate cyclase and FSH receptors was studied in hypophysectomized diethylstilbestrol-primed rats treated with FSH and/or the potent GnRH agonist [D-Ala6]des-Gly10-GnRH N-ethylamide (GnRHa). The animals were treated with 7.5 micrograms ovine FSH twice daily for 2 days, either alone or with 10 micrograms GnRHa. FSH-stimulated adenylate cyclase activity was augmented by 2.5- to 3.5-fold in the presence of 5'-guanyl-imidodiphosphate. Adenylate cyclase responses to FSH were almost completely abolished by GnRHa treatment in ovarian homogenates from control animals and rats treated with FSH. This inhibition was receptor specific, since GnRHa did not block adenylate cyclase stimulation by prostaglandin E2 or isoproterenol. No inhibition of 5'-guanyl-imidodiphosphate- or sodium fluoride-stimulated adenylate cyclase activity was noted after any hormone treatment. When GnRHa treatment was initiated at 12, 24, or 36 h during the 2-day period of FSH treatment, inhibition of both FSH- and LH-stimulated adenylate cyclase was observed in ovaries collected at 48 h. Whereas FSH treatment increased the ovarian FSH receptor concentration by more than 100%, concomitant treatment with GnRHa prevented this increase and reduced FSH receptors to 60% of the control level. Treatment with GnRHa alone caused a 65% decrease in FSH receptor levels below the untreated control values. Histological analysis of hormone-treated ovaries indicated that FSH stimulated follicle growth and antrum formation, but caused little luteinization. GnRHa did not completely prevent the effects of FSH on follicle growth, but did induce degeneration and premature cleavage of ova. GnRHa alone suppressed the diethylstilbestrol-stimulated mitotic activity, slightly increased degenerative changes in granulosa cells, and caused oocyte cleavage and premature antrum formation. These findings demonstrate that GnRHa inhibits FSH-dependent adenylate cyclase by a mechanism involving the loss of binding sites for FSH. It is also evident that only short term exposure to GnRHa is necessary for expression of the inhibitory action of the peptide upon FSH- and LH-stimulated adenylate cyclase.
 ...
PMID:Inhibitory actions of a gonadotropin-releasing hormone agonist on ovarian follicle-stimulating hormone receptors and adenylate cyclase in vivo. 629 48

The time and dose-response relationships of human follicle stimulating hormone (hFSH)-sensitive adenylate cyclase activity to hFSH binding was studied in the immature rat ovary following an sc injection of pregnant mare serum gonadotrophin (PMSG). When an optimal dose of PMSG (10 IU/rat) was administered, a marked increase in hFSH-sensitive activity was observed at day 2, followed by a sharp decline at day 3. This was accompanied by a parallel rise and fall in ovarian hFSH binding activity. When immature rats were given various doses (5-100 IU/rat) of PMSG for 2 days, hFSH-sensitive adenylate cyclase activity increased sharply and maximal stimulation was obtained at 10 IU/rat. A close correlation was also observed with respect to dose-response for hCG-sensitive adenylate cyclase and hCG binding activities. It is concluded that: 1) PMSG administration with an optimal dose to the immature rat induced ovarian FSH and LH-hCG receptors, and an adenylate cyclase system highly sensitive to hFSH and hCG, and 2) the acquisition and responsiveness of adenylate cyclase to gonadotrophins are closely related to the appearance and the numbers of gonadotrophin receptors.
 ...
PMID:Relationship of follicle stimulating hormone (FSH)-sensitive adenylate cyclase activity to FSH binding in immature rat ovaries following administration of pregnant mare serum gonadotrophin. 629 6

A rapid and marked amplification of LH and FSH-stimulated cyclic AMP accumulation and steroid secretion is produced by adenosine in luteal and granulosa cells, respectively, of both the rat and the human ovary. The rat Leydig cell response to LH, however, was unaffected by adenosine. In the luteal cell, adenine nucleotides and adenosine were equipotent with decreasing activity shown by inosine, adenine and hypoxanthine--guanosine, guanine, xanthine and pyrimidines were inactive. Both an extracellular and intracellular site appears to be involved in adenosine amplification of LH--the extracellular site accounted for about 20% of the response and may be a catalytic receptor site. The intracellular site was directly related to an increase in luteal cell ATP levels in which adenosine appears to serve as a selective prosubstrate for hormone activated adenylate cyclase. The luteal antigonadotropic action of PGF2 alpha was blocked by adenosine and these modulators were shown to be competitive antagonists of LH-stimulated cyclic AMP accumulation. Due to the ubiquitous nature of both adenosine and PGF2 alpha, (conditions have been described in other systems for their rapid release,) it is suggested that they may serve as important local humoral modulators of gonadotropin action for regulation and control of ovarian function.
 ...
PMID:Purine modulation of LH action in gonadal cells. 631 Feb 56

Gonadotropin treatment of the Sertoli cell produces a marked refractory state of the cell to subsequent hormonal stimulation. Because FSH also stimulates the phosphodiesterase activity of these cells, the possible involvement of an altered cAMP catabolism during refractoriness was investigated in an in vitro model. Sertoli cells, after 3 days of culture in a defined medium, were exposed to FSH or isoproterenol for 1-24 h. After this pretreatment, cells were stimulated for 1 h with a maximal FSH dose, and the responsiveness was measured in terms of cAMP accumulation. Sertoli cells previously treated with hormone entered a refractory state, a second exposure being ineffective in elevating intracellular or extracellular cAMP. Addition of the phosphodiesterase inhibitor 3-isobutyl-methylxanthine in the second incubation partially restored the ability of the cell to accumulate cAMP in the presence of hormone. This phosphodiesterase inhibitor also caused an apparent decrease in the potency of FSH to induce the refractory state. Such an impairment of response developed in the intact cell in 4 h, and was accompanied by a partial desensitization of the adenylate cyclase and an increase in phosphodiesterase activity. The stimulation of phosphodiesterase activity, but not the desensitization of adenylate cyclase, was inhibited by cycloheximide. The inhibition of protein synthesis also prevented the onset of the refractory state of the intact Sertoli cell. Pretreatment of the Sertoli cells with either FSH or isoproterenol rendered the cell refractory to a second stimulation with either agonist; in contrast, the adenylate cyclase desensitization in the homogenate was apparent only for the agonist employed in the preincubation. These results indicate that phosphodiesterase regulation is involved in the control of Sertoli cell responsiveness to hormone. Thus, the net decrease in cAMP production of the FSH-treated cells is the result of a decreased adenylate cyclase stimulation and an increased cAMP catabolism mediated by phosphodiesterase. The latter phenomenon appears to be the predominant cause of the partial refractoriness induced by low doses of gonadotropin.
 ...
PMID:Involvement of phosphodiesterase in the refractoriness of the Sertoli cell. 631 32


<< Previous 1 2 3 4 5 6 7 8 9 10