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)

Endocrine effects of cholera enterotoxin (CET) on male gonads were investigated in normal and hypophysectomized rats. After intratesticular injection of 5 micrograms of CET in the bilateral testes of normal rats, serum testosterone concentration remarkably increased after 24 hr, remained significantly elevated for at least 3 days and returned to the control level in 7 days. Serum LH level decreased in the undetectable range after 1--3 days; serum FSH level also significantly decreased after 3 days. Both gonadotropin levels increased 28 days after the injection, when the CET-injected testis decreased in weight and was accompanied by marked loss of germinal cells. When 5 micrograms of CET was injected intratesticularly in the bilateral testes of hypophysectomized rats, adenylate cyclase activity of a CET-injected testis was remarkably stimulated after 6 hr, remained four times elevated for at least 3 days and returned to the control level in 7 days. In relatively good accordance with the increase in adenylate cyclase activity, testosterone content remarkably enhanced in the CET-injected testis. These in vivo data indicate that the intratesticular injection of CET prolongedly stimulates the adenylate cyclase activity of testicular cells including Leydig cells and increases testosterone production, and suggest that the prolonged enzyme stimulation results in the sustained elevation of serum testosterone concentration for at least 3 days, causing the stimulation of the negative feedback mechanism of hypophysealtesticular axis to decrease serum LH levels in the undetectable range.
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PMID:Prolonged stimulation of adenylate cyclase activity and testosterone production by cholera enterotoxin with suppression of gonadotropin release in rats. 49 86

Numerous biochemical pathways influence the synthesis and release of anterior pituitary hormones. Releasing factors extracted from the hypothalamus and prostaglandins (PGs) appear to alter a common biochemical activity, adenyl cyclase, in pituitary cells. Luteinizing hormone releasing hormone (LRH), prostaglandin (PGE1), 7 oxa-13-prostynoic acid and cycloheximide were tested for individual and interacting effects on the in vitro release of FSH, LH and prolactin from hemipituitaries of 15 day old female rats. LRH (10 ng/ml) consistently released both LH and FSH in all in vitro experiments and inhibited prolactin release in 1 of 2 experiments. Lower concentrations (5 and 1 ng/ml) also stimulated LH and FSH release but did not influence prolactin release. Concurrent depletion of stored LH and FSH in the gland was observed. PGE1 in a 6.5 hour incubation increased the storage of LH within the gland in the absence of LRH. In a 1.5 hour incubation in the presence of LRH, storage of LH was also increased. PGE1 had no effect on LH and FSH release; however, in 1 of 2 experiments it stimulted prolactin release in the absence of LRH. Prostynoic acid stimulted LH and FSH release but did not synergize with LRH action in the same tissue. Cycloheximide did not affect LH release during the first 30 minutes of incubation; however, the release during the subsequent 1 hour was significantly inhibited. Similar tissue also exposed to cycloheximide was still responsive to LRH during the latter 1 hour incubation period. Cycloheximide had no effect on prolactin storage and release from the same tissue.
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PMID:Interactions of prostaglandin E1 (PGE1) and LRH on anterior pituitary function. 76 87

Human granulosa cells with differing steroidogenic potentials were cultured in vitro. The effects of prostaglandin F2alpha (PGF2alpha) and PGE2 on the progesterone output and viability of these cells were investigated. Prostaglandin F2alpha either alone or in combination with LH and FSH inhibited the production of progesterone over a wide range of concentrations (1-8000 ng/ml). However, the inhibitory effect of PGF2alpha was 200 times less effective when the cells were exposed to LH and FSH for 6 days before the addition of the prostaglandin. By contrast PGE2, at concentrations from 1 to 500 ng/ml, markedly stimulated the production of progesterone by granulosa cells, and this was not prevented by the addition of PGF2alpha. The degree of inhibition by PGF2alpha or stimulation by PGE2 was related to the biosynthetic capacity of the cells. These studies suggest that PGF2alpha may act directly on the adenylate cyclase system of human granulosa cells by blocking its activation by LH, and they demonstrate that functional regression of the luteal cell can be induced independently of the blood vascular system.
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PMID:Effects of prostaglandin F2alpha and E2 on the production of progesterone by human granulosa cells in tissue culture. 120 76

Glycoprotein hormones LH, FSH, TSH and hCG are heterodimeric molecules: each contains two subunits, a common alpha and a unique beta subunit. Each subunit bears one or two Asparagine linked carbohydrate moieties which have a biantennary complex-type or hybrid-type structure. Different technical methods as deglycosylation or molecular biology techniques have been used to study the role of carbohydrate residues in hormonal bioactivity. The carbohydrate chains are not directly involved in receptor binding events but their mechanisms of action is not fully understood. Two hypotheses are frequently emphasised: a conformational role or an involvement in the coupling of the receptor-adenylate cyclase system. At the post receptor level carbohydrate chains modulate the bioactivity in two ways: a global regulation following an all-or-none mode and slight one. The removal of the carbohydrate moieties leads to a loss of the in vitro hormonal activity. The results observed are dependent of the deglycosylation techniques and the bioactivity tests used. Hormone's deglycosylation reduces their capacity of production of cAMP and, to a lesser extent, their steroidogenic power. Deglycosylated hormones are antagonists to negative hormones although deglycosylated hCG has some agonist properties in vivo. Microheterogeneity of the glycoprotein hormones is due to slight variations in sialic acid and/or sulfate content. Glycoprotein hormones exist as several isoforms which differ in biological potency. Alkaline isoforms (less sialylated ones) are the most biologically active in vitro but have a short half live in vivo; acid isoforms are less active in vitro but have a longer circulatory half live. The polymorphism of glycoprotein hormones is a highly regulated process.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Glycoprotein hormones, glycosylation and biological activity]. 129 11

The maturation of ovarian granulosa cells is dependent upon the pituitary gonadotropin FSH, the actions of which are mediated via specific plasma membrane receptors. To study the regulation of ovarian FSH receptor expression at the mRNA level, we used a specific cRNA probe to evaluate changes in FSH receptor transcripts in cultured granulosa cells. Granulosa cells obtained from immature estrogen-treated rats contained two predominant FSH receptor mRNA transcripts (7.0 and 2.5 kilobases), the levels of which declined in a time-related manner during a 2-day culture period. However, inclusion of FSH (30 ng/ml) in the culture medium prevented the decline in FSH receptor mRNA levels. Compared to controls, treatment of granulosa cells for 48 h with FSH (1-100 ng/ml) increased FSH receptor mRNA levels in a dose-dependent manner (ED50, 4.5 ng/ml), with a maximal 5.9 +/- 0.7-fold increase observed in response to 30 ng/ml FSH. The stimulatory actions of FSH were mimicked by the adenyl cyclase activator forskolin (0.1-30 microM), suggesting the involvement of cAMP in FSH receptor gene transcription and/or mRNA stability. Incubation of granulosa cells for 48 h with epidermal growth factor (EGF; 0.3-10 ng/ml), basic fibroblast growth factor (bFGF; 1-30 ng/ml), or insulin-like growth factor-I (IGF-I; 1-30 ng/ml) did not affect basal FSH receptor mRNA levels, whereas the highest doses of EGF and bFGF, but not IGF-I, completely suppressed the stimulatory effects of FSH (30 ng/ml) on its own receptor mRNA levels. Similarly, GnRH (10-1000 nM) attenuated the actions of FSH on its receptor mRNA levels in a dose-dependent manner (ID50, 8 nM). The inhibitory effects of GnRH (100 nM) were reversed by cotreatment with a GnRH antagonist ([Ac-D-Phe1,D-pCl-Phe2,D-Trp3,6]GnRH; 100 nM), indicating that the actions of GnRH are mediated via specific GnRH receptors. These data indicate that treatment of granulosa cells with FSH increases the levels of two FSH receptor mRNA transcripts. However, this positive feedback system, which may lead to an amplification of FSH action, is tightly regulated by the inhibitory actions of EGF, bFGF, and GnRH. Thus, the use of cultured rat granulosa cells provides a model system to analyze the hormonal regulation of FSH receptor gene expression in the ovary.
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PMID:Hormonal regulation of follicle-stimulating hormone receptor messenger ribonucleic acid levels in cultured rat granulosa cells. 131 Dec 35

The effects of activin and inhibin on steroidogenesis in the human ovary were investigated. Granulosa cells harvested from follicles of women undergoing oocyte recovery for in vitro fertilization were maintained in culture for 4 days before treatment in serum-free medium. Human recombinant inhibin-A and activin-A at concentrations of 100 ng/mL did not affect basal progesterone secretion (P greater than 0.05). Progesterone concentrations were increased 2- to 6-fold by hCG or FSH. Activin-A inhibited the progesterone response to hCG compared with that of cells treated with hCG alone (P less than 0.01). The effect of activin-A was dose dependent and significant at 16-18 h of treatment (P less than 0.01). Inhibin-A at the same concentrations as activin-A had no effect on the progesterone responses to hCG and FSH. The hCG-induced accumulation of 20 alpha-hydroxyprogesterone was also attenuated by simultaneous activin-A treatment compared to that in cells treated with hCG alone (P less than 0.01). To investigate the mechanism of action of activin-A, cells were treated with a cAMP analog (8-bromo-cAMP) or an activator of adenylate cyclase (forskolin), with or without activin-A. Activin-A had no effect on 8-bromo-cAMP-stimulated progesterone accumulation. Likewise, forskolin-stimulated progesterone accumulation was not affected by activin-A. The hCG-induced increase in intracellular cAMP was decreased by activin-A in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine (P less than 0.01). Thus, activin-A may inhibit progesterone production by suppression of gonadotropin-induced cAMP production. These results support an autocrine role of activin-A in the steroidogenic capacity of human ovarian cells.
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PMID:Inhibition of progestin accumulation by activin-A in human granulosa cells. 132 53

The ligand specificity and biochemical properties of the human (h) FSH receptor are poorly characterized due to the low abundance of these receptors and the limited availability of human tissues. Using a fragment of rat FSH receptor cDNA, we screened a human testicular cDNA library and obtained a FSH receptor cDNA covering the entire amino acid-coding region. After transfection of a human fetal kidney cell line (293) with the hFSH receptor cDNA, radioligand receptor analysis revealed the presence of high affinity (Kd, 1.7 x 10(-9) M) FSH-binding sites on the plasma membrane. Both recombinant and wild-type hFSH displaced [125I]hFSH binding, with ED50 values of 25 and 70 ng/ml, respectively, whereas hLH, hCG, and hTSH were ineffective. Although human, rat(r), and ovine FSH as well as equine CG competed for rat testicular FSH receptor binding, only hFSH and rFSH interacted effectively with the recombinant hFSH receptor, suggesting that species-specific ligand recognition exists between human and rodent receptors. After incubation of transfected cells with hFSH, but not recombinant hLH or hCG, a dose-dependent increase (ED50, 10 ng/ml) in extracellular cAMP accumulation was observed, indicating a functional coupling of the expressed human receptor with the endogenous adenyl cyclase. In cells cotransfected with the FSH receptor expression plasmid and a luciferase reporter gene driven by the promoter of a cAMP-responsive gene, treatment with hFSH, but not hCG, resulted in a dose-dependent increase in luciferase activity. Northern blot analysis using a cRNA probe derived from the human receptor cDNA indicated the presence of multiple FSH receptor mRNA transcripts (7.0, 4.2, and 2.5 kilobases) in RNA prepared from human follicular phase ovary, but not from human corpus luteum or placenta. Additionally, two FSH-binding sites of 76 and 112 kilodaltons were detected in transfected 293 cells after ligand/receptor cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. These results demonstrate the expression of functional hFSH receptor with unique ligand specificity and provide new data on the biochemical properties of the human receptor at the mRNA and protein levels.
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PMID:Expression of recombinant human follicle-stimulating hormone receptor: species-specific ligand binding, signal transduction, and identification of multiple ovarian messenger ribonucleic acid transcripts. 132 83

Pituitary adenylate cyclase-activating peptide (PACAP), a novel hypothalamic peptide that has been shown to exist in several tissues including the testis, was examined for its effects on cultured rat Sertoli cells. PACAP stimulates cAMP accumulation in Sertoli cells cultured from 15-day-old rats in the presence or absence of methylisobutylxanthine, a phosphodiesterase inhibitor, and in the presence of pertussis toxin, a blocker of the adenylate cyclase inhibitory pathway. Maximal stimulation, which is 20-40% of that attainable with FSH, occurs at PACAP concentrations of 10 nM: the ED50 is approximately 100 pM. The ability of PACAP to stimulate Sertoli cell cAMP declines with increasing age of donor animals (15-60 days of age) in a fashion similar to the FSH effect. PACAP stimulation of Sertoli cell cAMP accumulation is additive with submaximal, but not maximal, concentrations of FSH or forskolin. PACAP also stimulates the secretion of lactate, estradiol, and inhibin in a concentration-dependent manner. The stimulation of Sertoli cell cAMP accumulation by PACAP is not altered by a vasoactive intestinal peptide antagonist, and vasoactive intestinal peptide alone does not stimulate cAMP accumulation, indicating that PACAP is not acting via vasoactive intestinal peptide receptors. Further experiments are needed to determine whether PACAP is synthesized within the testis and if so, in which cell types; however, the present data clearly demonstrate that PACAP can modulate Sertoli cell function in vitro.
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PMID:A novel hypothalamic peptide, pituitary adenylate cyclase activating peptide, modulates Sertoli cell function in vitro. 133 66

The regulation of steroidogenesis in both the ovary and testis involves a complex interaction of a diversity of hormones and intracellular signaling pathways. The recent cloning of LH and FSH receptors has paved the way for an increased understanding of the mechanisms of receptor conformation, ligand-receptor interaction, and facilitation of post-receptor activity. The dominant role played by LH in the regulation of steroid production appears to be mediated by more than one intracellular signaling pathway. In addition to the stimulation of the adenylate cyclase-cAMP pathway, also known to be stimulated by FSH, the actions of LH may be additionally mediated by other intracellular messengers, such as those derived from the PLC pathway. Steroidogenesis in the gonads appears to be modulated by a variety of factors in addition to the gonadotropins. In this review, those factors of intracellular signaling mechanisms of which we have some understanding have been discussed. These include GnRH, PGF2 alpha, Ang II, VIP, GHRH, TNF alpha, CRF, EGF, and TGF alpha. Many of these factors have been shown to be locally synthesized, and specific receptors have been identified in the gonads. Many gonadal factors have the capacity to exert effects on steroidogenesis independent of the gonadotropins. Alternately, they have been demonstrated to alter the gonadal response to the gonadotropins via autocrine, paracrine, and intracrine mechanisms. As yet, our understanding of the intracellular signaling mechanisms used by novel gonadal regulators is limited. The involvement of the PLC, PLA2, and PLD pathways in this regard has been reviewed. It is becoming apparent that multiple signaling pathways may be stimulated by a single hormone, as in the case of GnRH, PGF2 alpha, and LH. The complexity of intracellular signal transduction in the gonads is enhanced by the potential cross-talk at numerous steps in the signaling cascades.
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PMID:Intracellular signaling in the gonads. 142 84

We have previously described FSH receptor-mediated influx of 45Ca++ in cultured Sertoli cells from immature rats and receptor-enriched proteoliposomes via activation of voltage-sensitive and voltage-independent calcium channels. We have further shown that this effect of FSH does not require cholera toxin- or pertussis toxin-sensitive guanine nucleotide binding protein or activation of adenylate cyclase. In the present study, we have identified regions of human FSH-beta-subunit which appear to be involved in mediating calcium influx. We screened 11 overlapping peptide amides representing the entire primary structure of hFSH-beta-subunit for their effects on 45Ca++ flux in FSH receptor-enriched proteoliposomes. hFSH-beta-(1-15) and hFSH-beta-(51-65) induced uptake of 45Ca++ in a concentration-related manner. This effect of hFSH-beta-(1-15) and hFSH-beta-(51-65) was also observed in liposomes lacking incorporated FSH receptor, suggesting that the peptide amides may act as ionophores or channel-formers. Reducing membrane fluidity by incubating liposomes (containing no receptor) with hFSH-beta-(1-15) or hFSH-beta-(51-65) at temperatures lower than the transition temperatures of their constituent phospholipids resulted in no significant (P greater than 0.05) difference in 45Ca++ uptake. The effectiveness of the calcium ionophore A23187, however, was abolished. Ruthenium red, a voltage-independent calcium channel antagonist, was able to completely block uptake of 45Ca++ induced by hFSH-beta-(1-15) and hFSH-beta-(51-65) whereas nifedipine, a calcium channel blocker specific for L-type voltage-sensitive calcium channels, was without effect. These results suggest that in addition to its effect on voltage-sensitive calcium channel activity, interaction of FSH with its receptor may induce formation of transmembrane aqueous channels which also facilitate influx of extracellular calcium.
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PMID:Synthetic peptides corresponding to human follicle-stimulating hormone (hFSH)-beta-(1-15) and hFSH-beta-(51-65) induce uptake of 45Ca++ by liposomes: evidence for calcium-conducting transmembrane channel formation. 164 50


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