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 desensitization of follicle-stimulating hormone (FSH)-evoked cAMP synthesis occurs upon continuous or repeated hormonal stimulation, and it involves the hormone-receptor interaction and post-receptor events. These mechanisms were studied in a murine granulosa cell line (KK-1) stably transfected with the human FSH receptor (hFSHR) complementary deoxyribonucleic acid (cDNA) under a powerful viral promoter. Hence, the FSHR transcriptional regulation was eliminated from the experimental model. Stimulation of the cells with recombinant human FSH (rhFSH) or a phorbol ester, 12-O-tetradecanoylphorbol-13 acetate (TPA), resulted in clear desensitization, i.e. subsequent rhFSH-stimulated cAMP formation was 73.4 +/-2.2%, (P < 0.001) and 66.3 +/-3.4%, (P < 0.0001), respectively, of that of cells preincubated in medium. TPA prestimulation evoked also clear inhibition (65-74% of control) of rhFSH or forskolin (a non-specific activator of adenylate cyclase) induced progesterone production. The suppression by TPA preincubation of the rhFSH-induced cAMP synthesis was completely abolished by the protein kinase C (PKC) inhibitor staurosporine (STR). Preincubation with STR exhibited a significant (P < 0.0001) increasing effect on the rhFSH-stimulated cAMP accumulation. The specific involvement of PKC was further evidenced by other inhibitors, all of them exerted significant elevation of cAMP synthesis following rhFSH restimulation. Furthermore, only the PKC beta isoform appeared to be constitutively expressed in these cells during desensitization. Prestimulation of the G-protein activity by sodium fluoride (NaF) or cholera toxin (CT), followed by rhFSH challenge, accounted for a decrease in the cAMP-mediated responsiveness, down to 69.4 +/- 2.8 or 74.2 +/- 1.9%, of control (P < 0.001), respectively, indicating that the post-receptor events are critical for desensitization. [125I]iodo-rhFSH binding to the cells did not change significantly during desensitization and the different stimulations. In contrast, approximately 50% increase (P < 0.001) occurred in the steady-state levels of FSHR mRNA in the cells stimulated with FSH. This was apparently due to prolonged half-time of mRNA, and not to altered transcription, since the FSHR cDNA was driven by a powerful viral promoter. In accordance, the cells transfected with Simian Virus (SV40) promoter-driven luciferase gene did not display alterations in luciferase activity following stimulatory treatments. The effects of the post-receptor stimulations (NaF or CT) on [125I]iodo-rhFSH binding were minor (8-12% reduction). Taken together, these data provide evidence that the agonist-responsive hFSHR desensitization appears through a PKC-beta isoform-mediated modulation of cAMP production. The desensitization of FSH action involves modifications of functional properties of the existing components of the FSH signal transduction complex, and does not require concomitant suppression of transcription or translation of the FSHR gene.
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PMID:Mechanisms of desensitization of follicle-stimulating hormone (FSH) action in a murine granulosa cell line stably transfected with the human FSH receptor complementary deoxyribonucleic acid. 1002 74

The process of ovarian folliculogenesis is composed of proliferation and differentiation of the constitutive cells in developing follicles. Growth factors emitted by oocytes integrate and promote this process. Growth differentiation factor-9 (GDF-9), bone morphogenetic protein (BMP)-15, and BMP-6 are oocyte-derived members of the transforming growth factor-beta superfamily. In contrast to the recent studies on GDF-9 and BMP-15, nothing is known about the biological function of BMP-6 in the ovary. Here we show that, unlike BMP-15 and GDF-9, BMP-6 lacks mitogenic activity on rat granulosa cells (GCs) and produces a marked decrease in follicle-stimulating hormone (FSH)-induced progesterone (P(4)) but not estradiol (E(2)) production, demonstrating not only the first identification of GCs as BMP-6 targets in the ovary but also its selective modulation of FSH action in steroidogenesis. This BMP-6 activity resembles BMP-15 but differs from GDF-9 activities. BMP-6 also exhibited similar action to BMP-15 by attenuating the steady state mRNA levels of FSH-induced steroidogenic acute regulatory protein (StAR) and P450 side-chain cleavage enzyme (P450scc), without affecting P450 aromatase mRNA level, supporting its differential function on FSH-regulated P(4) and E(2) production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced P(4) production and StAR and P450scc mRNA expression. BMP-6 also decreased FSH- and forskolin-stimulated cAMP production, suggesting that the underlying mechanism by which BMP-6 inhibits FSH action most likely involves the down-regulation of adenylate cyclase activity. This is clearly distinct from the mechanism of BMP-15 action, which causes the suppression of basal FSH receptor (FSH-R) expression, without affecting adenylate cyclase activity. As assumed, BMP-6 did not alter basal FSH-R mRNA levels, whereas it inhibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies provide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.
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PMID:Biological function and cellular mechanism of bone morphogenetic protein-6 in the ovary. 1144 21

The effect of dexamethasone on follicle-stimulating hormone (FSH)-stimulated expression of cholesterol side-chain cleavage (P450scc) enzyme and production of progesterone by ovarian granulosa cells was studied in vitro. Granulosa cells from 3- to 5-mm pig antral follicles were cultured for 48 h in the presence or absence of FSH and/or dexamethasone. Treatment with FSH resulted in a dose-dependent increase in the level of P450scc mRNA that reached a submaximum at 100 ng FSH/ml. This increase was associated with an increase in progesterone production. Treatment of the cells with increasing concentrations (10(-9)-10(-6) M) of dexamethasone for 48 h increased constitutive and potentiated FSH-stimulated P450scc mRNA levels and progesterone production in a dose-dependent manner. Increasing duration (12-48 h) of treatment with dexamethasone (100 nM) led to a time-dependent increase in basal and FSH-stimulated progesteorne production, achieving statistical significance by 48 and 24 h, respectively. Dexamethasone also increased P450scc mRNA level and progesterone production induced by the adenylate cyclase activator forskolin (10 microM) or a cAMP analog 8-Br-cAMP (1 mM). The effects of dexamethasone on FSH-induced progesterone production were blocked by cotreatment of the cells with glucocorticoid receptor antagonist RU-486. These results demonstrate that dexamethasone potentiates FSH actions on steroidoogenesis in the pig ovary. Possible mechanisms for this potentiation include the ability of dexamethasone to stimulate P450scc gene expression.
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PMID:Dexamethasone enhances follicle stimulating hormone-induced P450scc mRNA expression and progesterone production in pig granulosa cells. 1176 83

The unique reproductive patterns, delayed fertilization in females, and asynchrony between spermatogenesis and mating behavior in males are well documented in bats living in temperate latitudes. The present study was undertaken to examine follicle-stimulating hormone (FSH) receptors in the testis of bats, Rhinolophus ferrumequinum, during the annual reproductive cycle. Male bats were captured at natural roosting sites and testicular preparations were subjected to a radioligand binding assay for FSH receptors. The weight of paired testes increased considerably in the spermatogenic period and decreased from the mating to hibernation periods. Meiotic division in the testis was observed in the spermatogenic period but not the mating period. Serum testosterone concentrations increased in the spermatogenic period and rapidly decreased in the mating period. The binding of FSH was specific for mammalian FSHs and detected primarily in the testis. Scatchard plot analyses of the binding of FSH to bat testicular preparations showed straight lines, suggesting the presence of a single class of binding sites. The affinities (equilibrium association constant) of FSH receptors were consistent throughout the annual reproductive cycle. The specific binding per unit weight of testis and total binding in the paired testes were highest in the mating period and in the spermatogenic period, respectively, among reproductive periods. The accumulation of cyclic adenosine 3', 5'-monophosphate to FSH stimulation was higher in the spermatogenic period than in the hibernation period. These findings suggest that testicular function of bats is associated with seasonal changes in the number of binding sites, while the number per target cell and the activation of adenylate cyclase led by FSH-receptor complex considerably decreases in the hibernation period.
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PMID:Basic properties and annual changes of follicle-stimulating hormone receptors in the testis of horseshoe bats, Rhinolophus ferrumequinum. 1185 64

In mammals, gonadal functions are regulated by two pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), that interact with gonadal membrane receptors to activate adenylate cyclase. In comparison to mammalian systems, in squamate reptiles a reduced amount of information exists on gonadotropins and their related receptors. This study is aimed at clarifying if, in the lizard Podarcis sicula, the ovarian sensitivity to FSH is correlated to the reproductive cycle and to the expression of membrane receptors involved in the hormone recognition. The results demonstrate that the ovarian adenylate cyclase responsiveness to FSH parallels ovarian functions, being maximal during the ovulatory period. The ovarian sensitivity to FSH is also related to oocyte growth and vitellogenesis. Northern blot analyses reveal that the FSH receptor mRNA is maximally expressed in vitellogenic oocytes during the reproductive period. These results suggest that, in lizard ovary, hormone activation of adenylate cyclase is mediated by de novo synthesis of receptors specifically involved in FSH recognition. In lizards treated in vivo with FSH during the pre-ovulatory period, adenylate cyclase becomes refractory to further FSH stimulation 2 hr after treatment, but sensitivity to the hormone is restored after 2 weeks. Nevertheless, while the restored level of activity never exceeds that observed during the nonreproductive period, the expression level of FSH receptor mRNAs is significantly enhanced in these animals. These results suggest that in lizard the processes that regulate ovarian growth, vitellogenesis, and ovulation are controlled by a complex network of signals including gonadotropin, FSH receptor expression, and adenylate cyclase.
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PMID:Relationship between adenylate cyclase sensitivity to follitropin and FSH receptor mRNA expression in the ovary of the lizard Podarcis sicula. 1198 31

The aim of this study was to investigate the effect of short-term treatment (first 2 or 6 h) with recombinant human follicle-stimulating hormone (r-hFSH) during in vitro maturation (IVM) on the developmental competence of bovine oocytes. The roles of protein kinase A (PKA) and protein kinase C (PKC) (possibly involved in FSH response), were investigated using activators (Sp-cAMPS, PMA) or inhibitors (Rp-cAMPS, sphingosine) of these two protein kinases, respectively. The developmental competence of bovine oocytes was measured by the rate of blastocyst formation after in vitro fertilization (IVF). Our results showed that when cumulus-oocyte complexes (COCs) were cultured with r-hFSH for the first 6 h, a highly significant (P < 0.0001) improvement is seen in blastocyst development rate as a proportion of oocytes in culture compared with those matured with r-hFSH for the first 2 or 24 h. A transient exposure (6 h) to the highest dose (100 microM) of forskolin (an activator of adenylate cyclase) increased (P < 0.05) the rate of blastocyst formation. But the PKA inhibitors (Rp-cAMPS) did not affect the stimulatory effects of r-hFSH on the blastocyst yield. However, stimulation of PKC by low doses of PMA (0.1-0.5 microM) during short-term treatment, enhanced (P < 0.0001) the developmental capacity of oocytes, while sphingosine (a specific inhibitor of PKC) inhibited (P < 0.05) the stimulatory effects of r-hFSH on the rate of blastocyst formation. Our results indicate that although the developmental capacity of bovine oocytes in vitro can be modulated by both the PKA, and the PKC pathways, the activation of PKC during short-term treatment can mimic the effect of r-hFSH on the cytoplasmic maturation in bovine oocytes in vitro.
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PMID:Protein kinases influence bovine oocyte competence during short-term treatment with recombinant human follicle stimulating hormone. 1612 37

Adenylate cyclase-activating polypeptide 1 (ADCYAP1) binds both Gs- and Gq-coupled receptors and stimulates adenylate cyclase/cAMP and protein kinase C/mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathways in pituitary gonadotrophs. In this study, we investigated the cAMP and MAPK3/1 signaling pathways induced by ADCYAP1 stimulation and examined the effects of ADCYAP1 on the expression of gonadotropin subunit genes using a clonal gonadotroph cell line, LbetaT2. ADCYAP1 increased intracellular cAMP accumulation up to 19-fold in LbetaT2 cells. Common alpha-glycoprotein subunit gene (Cga) promoter activity was strongly activated by both ADCYAP1 and the cyclic-AMP analog, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Both had little effect on luteinizing hormone beta (Lhb) and follicle-stimulating hormone beta (Fshb) promoter activities. Cga promoter activity was significantly increased by transfection with constitutively active cAMP-dependent protein kinase (PKA). Activities of the Lhb and Fshb promoters were only modestly increased. Both ADCYAP1 and CPT-cAMP induced MAPK3/1 activation in LbetaT2 cells. The MEK inhibitor, U0126, and the PKA inhibitors, H89 and cAMP-dependent protein kinase peptide inhibitor (PKI), completely inhibited MAPK3/1 activation by either ADCYAP1 or CPT-cAMP. Using luciferase reporter constructs containing cis-elements, the cAMP response element (Cre) promoter was stimulated about 4-fold by ADCYAP1. ADCYAP1-induced Cre promoter activity was completely inhibited by H89, but not by U0126. ADCYAP1 also increased the activity of the serum response element (Sre) promoter, a target for MAPK3/1, and treatment of the cells with U0126 completely inhibited ADCYAP1-induced Sre promoter activity. ADCYAP1-increased Cga promoter activity was inhibited partially by both H89 and U0126. Although combining the inhibitors showed an additive inhibition effect, it did not result in complete inhibition. These results suggest that in LbetaT2 cells, ADCYAP1 mainly increases Cga through activation of PKA and MAPK3/1, as well as through an additional unknown pathway.
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PMID:Cyclic adenosine 3',5'monophosphate/protein kinase A and mitogen-activated protein kinase 3/1 pathways are involved in adenylate cyclase-activating polypeptide 1-induced common alpha-glycoprotein subunit gene (Cga) expression in mouse pituitary gonadotroph LbetaT2 cells. 1759 63

There is increasing evidence for communication among pituitary cells. Hormone-producing pituitary cells may communicate with each other and with folliculostellate cells. The latter cells surround pituitary hormone-producing cells and are connected by tight junctions to form a network that allows for their coordinated function. Folliculostellate cells are targets of cytokines, peptides, and steroid hormones, and produce growth factors and cytokines, including follistatin, the dynamic regulator of follicle-stimulating hormone (FSH) production that binds activin, and limits activin signaling. Pituitary adenylate cyclase-activating peptide (PACAP) and its receptor are found in folliculostellate cells in which they stimulate transcription of the follistatin gene through cyclic adenosine monophosphate/protein kinase A (PKA) signaling. When PACAP increases, follistatin levels increase, and FSH-beta mRNA is reduced. PACAP also activates gonadotrophs to stimulate transcription of the gonadotropin alpha-subunit gene and lengthen the LH-beta mRNA, presumably to prolong it half-life, and increases responsiveness to GnRH. Accordingly, PACAP differentially regulates FSH and LH, and may prove to be a key player in reproduction through a novel paracrine mechanism.
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PMID:Paracrine control of gonadotrophs. 1771 Jul 34

The follicle-stimulating hormone is critical to reproductive success and is an important target for development of novel reproductive therapies. We have recently reported the development of thiazolidinone positive allosteric modulators of the follicle-stimulating hormone receptor. Here, we demonstrate that discrete modifications in the chemical structure of the thiazolidinone agonists produced compounds with different pharmacological properties. Positive allosteric modulators activated adenylate cyclase signaling (Gs). Using an ADP-ribosylation assay we found that both differing glycosylated variants of human FSH (hFSH) and selected thiazolidinone allosteric modulators of the FSHR induce activation of the Gi signaling pathway. Additionally, we observed that some analogs of this class could activate both pathways. These data suggest that the pharmacological activity of thiazolidinone modulators to the FSHR may be due to the ability of these compounds to induce association of the FSHR with either Gs or Gi signaling pathways in an analog-specific manner.
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PMID:Differing pharmacological activities of thiazolidinone analogs at the FSH receptor. 1825 97

We examined how pulsatile stimulation with adenylate cyclase-activating polypeptide 1 (ADCYAP1) affected gonadotrophs. In static culture, gonadotropin-releasing hormone (GnRH) stimulated transcription of all the gonadotropin subunits. In contrast, ADCYAP1 increased common alpha-glycoprotein subunit gene (Cga) promoter activity but failed to increase luteinizing hormone beta (Lhb) and follicle-stimulating hormone beta (Fshb) promoters. Messenger RNAs for Lhb and Fshb were slightly but significantly increased by ADCYAP1 stimulation. The results of cotreatment of the cells with GnRH and ADCYAP1 was not different from the effects of GnRH alone on Lhb and Fshb transcriptional activities as well as on mRNA expressions. To determine the effect of pulsatile ADCYAP1 stimulation on gonadotropin subunit gene expression, perifused LbetaT2 cells were stimulated either at high frequency (5-min ADCYAP1 pulse every 30 min) or at low frequency (5-min ADCYAP1 pulse every 120 min). High-frequency ADCYAP1 pulses preferentially increased Lhb gene expression 2.29-fold +/- 0.15-fold, and low frequency pulses resulted in a 1.55-fold +/- 0.16-fold increase. Fshb gene expression was increased 1.87-fold +/- 0.3-fold by high-frequency ADCYAP1 pulses and 4.3-fold +/- 0.29-fold by low-frequency pulses. These results were similar to the frequency-specific effects of pulsatile GnRH. Follistatin (Fst) gene expression was specifically increased by high-frequency GnRH pulses. High-frequency ADCYAP1 pulses increased Fst to a larger extent (4.7-fold +/- 0.57-fold) than did low-frequency pulse (2.72-fold +/- 1.09-fold). ADCYAP1 receptor gene (Adcyap1r) expression was increased significantly following pulsatile GnRH regardless of pulse frequency. Low-frequency ADCYAP1 pulses, however, increased Adcyap1r expression (16.49-fold +/- 8.41-fold) to a larger extent than high frequency pulses did. In addition, high-frequency ADCYAP1 pulses specifically increased Gnrhr (GnRH receptor) expression by 4.38-fold +/- 0.81-fold; however, low-frequency pulses did not result in an increase. These results suggest that ADCYAP1, like GnRH, specifically regulates Lhb and Fshb subunit gene in a pulse frequency-specific manner. This regulation may involve alteration in numbers of GnRH and ADCYAP1 receptors as well as FST expression.
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PMID:Pulse frequency-dependent gonadotropin gene expression by adenylate cyclase-activating polypeptide 1 in perifused mouse pituitary gonadotroph LbetaT2 cells. 1945 15


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