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)

Cells of the 7315c tumor released immunoreactive PRL (IR-PRL). Cholera toxin enhanced this release. Morphine and other opiate agonists inhibited IR-PRL release from both untreated and cholera toxin-treated tumor cells. The opiate-induced inhibition of IR-PRL release was concentration dependent and naloxone sensitive. Cholera toxin also enhanced the adenylate cyclase activity of 7315c tumor tissue. Opiates inhibited enzyme activity in both untreated and cholera toxin-treated 7315c tissue in a concentration-dependent and naloxone-sensitive manner. FK 33824 was more potent than [D-Ala2,D-Leu5]enkephalin in inhibiting IR-PRL release and adenylate cyclase activity. In cholera toxin-treated 7315c tumor tissue, GTP was required for opiate-induced inhibition of adenylate cyclase activity. Nonhydrolyzable analogs of GTP inhibited toxin-stimulated cyclase activity in the absence of an opiate. These results suggest that the 7315c tumor possesses a mu-opiate receptor; stimulation of this receptor inhibits both IR-PRL release and adenylate cyclase activity. An inhibitory guanyl nucleotide component may link the mu-opiate receptor to adenylate cyclase.
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PMID:A mu-opiate receptor in 7315c tumor tissue mediates inhibition of immunoreactive prolactin release and adenylate cyclase activity. 609 35

Somatostatin (SRIF) has previously been shown to inhibit both basal and hormone-stimulated PRL secretion from GH4C1 cells, a clonal strain of rat pituitary tumor cells. In this study we examined the ability of SRIF to modulate cAMP accumulation in GH4C1 cells to determine whether such alterations mediate its biological effects. SRIF did not cause statistically significant changes in basal cAMP accumulation. Of six PRL secretagogues examined, only vasoactive intestinal peptide (VIP) increased cAMP accumulation significantly: TRH, bombesin, epidermal growth factor, insulin, and the tumor promoter, phorbol-12,13-dibutyrate were without effect. When SRIF was added simultaneously with VIP, it inhibited maximal VIP-stimulated cAMP accumulation (55 +/- 3%, mean +/- SE) without changing the ED50 for VIP (3.0 +/- 0.2 nM). Inhibition by SRIF was not due to altered kinetics of VIP stimulation, since the half-time for VIP-stimulated cAMP accumulation was 2 min both in the absence and presence of 100 nM SRIF. SRIF did not inhibit isobutylmethylxanthine-stimulated cAMP accumulation, and the presence of 0-10 mM isobutylmethylxanthine did not alter the inhibitory effect of SRIF on VIP-stimulated cAMP accumulation. Therefore, SRIF must act primarily to modulate VIP activation of adenylate cyclase activity. Inhibition of VIP-stimulated cAMP accumulation occurred at concentrations of SRIF (ID50 = 1.2 +/- 0.1 nM) close to the equilibrium dissociation constant for receptor binding (Kd = 0.6 +/- 0.2 nM). Furthermore, the potencies of a series of SRIF analogs to inhibit VIP-stimulated cAMP accumulation correlated with the apparent Kd of each peptide for binding to the SRIF receptor. In addition, SRIF did not reduce VIP-stimulated cAMP accumulation in GH(1)2C1 cells, which lack SRIF receptors. We conclude that SRIF inhibits VIP-stimulated cAMP accumulation by a receptor-mediated process that may be causally related to the ability of SRIF to inhibit VIP-dependent PRL secretion.
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PMID:Somatostatin inhibits vasoactive intestinal peptide-stimulated cyclic adenosine monophosphate accumulation in GH pituitary cells. 619 74

Rat anterior pituitaries were incubated for 20 min with 1, 5 or 20 nmol TRH ml-1 and cAMP was measured in the homogenate of pituitary tissue after incubation, while TSH and PRL release into the medium was estimated with the aid of specific radioimmunoassay. In a similar experiment the activity of adenylate cyclase in pituitary homogenates was measured after the incubation with 0.5, 1.0 or 5.0 nmol TRH ml-1. Significant increase of TSH and PRL in the medium was found after 5 and 20 nmol TRH ml-1, while cAMP was significantly increased after 20 nmol TRH ml-1 only. The activity of adenylate cyclase was significantly increased after all doses of TRH used. In general, these findings are consistent with current views on the effect of hypothalamic hormones via adenylate cyclase - cAMP system and show that the responsiveness and sensitivity of an in vitro system using whole pituitaries appears to be less that of in vivo system.
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PMID:In vitro effect of TRH on adenylate cyclase and cAMP in rat anterior pituitary and on TSH and PRL release into incubation medium. 625 79

The mechanism by which PRL acts on ovarian interstitial cells to inhibit androgen synthesis was examined using primary cultures of ovarian cells from hypophysectomized immature rats grown in serum-free medium. In the presence of LH, the cultured interstitial cells showed a 200-fold increase in androgen production, of which androsterone was the principal metabolite. The addition of highly purified PRL (100 ng/ml) markedly inhibited (98%) the LH-stimulated androsterone accumulation. The ED50 of PRL action was calculated to be 1.3 +/- 0.4 ng/ml. The inhibition of androsterone production by PRL was rapid (t 1/2 = 75 min), not readily reversible, and could be evoked at any time during the culture period. The effects of PRL on LH-stimulated androgen production were not due to changes in [125I]iodo-hCG binding. LH-stimulated adenylate cyclase, cell number, or cell viability. As with LH, prostaglandin E2, cholera toxin, or 8-bromo cAMP also caused marked increases in androsterone synthesis, and these effects were blocked (98-99%) by PRL. Studies on the metabolism of steroid hormones revealed that PRL decreased LH-stimulated androsterone and 5 alpha-androstane-3 alpha, 17 beta-diol accumulation by 99%, androstenedione by 94%, testosterone by 90%, dehydroepiandrosterone by more than 80%, pregnenolone and 17 alpha-hydroxyprogesterone by 80%, 17 alpha-hydroxypregnenolone by 84%, and progesterone by 71%. Binding experiments demonstrated the presence of a single class of high affinity (Kd = 2.42 x 10(10) M), low capacity (2.37 fmol/10(6) cells) [125I]iodo-PRL-binding sites in the interstitial cells, suggesting that such receptors mediate the inhibitory action of PRL. It is inferred from these results that PRL antagonizes the stimulatory effects of LH on ovarian androgen biosynthesis by inhibiting a step distal to cAMP formation and before or at the cholesterol side-chain cleavage step.
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PMID:Prolactin inhibition of luteinizing hormone-stimulated androgen synthesis in ovarian interstitial cells cultured in defined medium: mechanism of action. 629 6

Calcium (Ca2+) ionophore A23187 increased the intracellular cAMP content and PRL release in normal rat anterior pituitary cells. Cotreatment with dopamine reduced both control and A23187-stimulated cAMP accumulation and PRL release. The dopamine antagonist spiperone restored the response of cAMP to ionophoric stimulation after pretreatment with dopamine in the greatest concentration used. Penfluridol, a compound with Ca2+-calmodulin-blocking properties, decreased control and A23187-stimulated cAMP content and PRL release. W7, a selective calmodulin-blocking agent, reduced basal cAMP and PRL release, whereas W5, a W7 analog with only 20% of its calmodulin-blocking ability, did not affect cAMP or PRL secretion. These data indicate that the Ca2+-calmodulin and cAMP systems are interrelated in the regulation of PRL secretion. They are also consistent with the hypothesis that the inhibition of PRL release by dopamine occurs after Ca2+ is mobilized and when or before it stimulates adenylate cyclase activity.
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PMID:Adenosine 3',5'-monophosphate (cAMP) and calcium-calmodulin interrelation in the control of prolactin secretion: evidence for dopamine inhibition of cAMP accumulation and prolactin release after calcium mobilization. 629 10

We investigated the role of Ca++ in cAMP-stimulated PRL release from 1) primary cultures of male rat pituitary glands, 2) primary cultures of estrogen-induced pituitary tumors from Fischer rats, and 3) the pituitary tumor cell line GH4C1. Forskolin, an activator of adenylate cyclase, increased intracellular cAMP concentrations in GH4C1 cells at least 20-fold within 15 min. This increase occurred in the presence or absence of added extracellular Ca++ or in the presence of D600 or Co++. Forskolin increased PRL release from the three types of cells. The three systems differed in the Ca++ sensitivity of forskolin-induced release, but showed little difference in the Ca++ sensitivity of K+-induced release. This was shown in two ways. The cells were incubated either 1) in a medium without added Ca++ or 2) in the presence of a Ca++ channel inhibitor, D600. In normal cells, K+- and forskolin-induced release were equally inhibited when extracellular Ca++ was removed or D600 was added. In GH4C1 cells, Ca++ removal or D600 addition (100 microM) completely blocked K+-induced release, but had little effect on forskolin-induced release. The response of Fischer tumor cells was intermediate between those of normal and GH4C1 cells. 45Ca++ uptake by GH4C1 cells was not affected by forskolin, whereas the release of 45Ca++ from preloaded cells was increased slightly only 30 min after the addition of forskolin in three of four experiments. The difference in Ca++ requirements between normal and GH4C1 cells for forskolin stimulation may be due to the release of cellular Ca++ stores by cAMP. These stores may not be as large in normal cells as they are in GH4C1 cells, and therefore the requirement for extracellular Ca++ occurs. Alternatively, GH4C1 cells may release PRL by a mechanism different from that which normal cells use.
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PMID:Difference in calcium requirements for forskolin-induced release of prolactin from normal pituitary cells and GH4C1 cells in culture. 632 46

The in vivo regulation of ovarian gonadotropin and prolactin receptors and adenylate cyclase activity by FSH, and the potent GnRH agonist [D-Ala6]des-Gly10-GnRH N-ethylamide (GnRHa), was studied in immature hypophysectomized diethylstilbestrol-implanted rats. During FSH treatment over a 48 h period, FSH receptors increased 2-fold with the maximum response during the first 12 h, whereas LH and prolactin receptors increased by 10-fold and 6-fold with the maximum response from 12 to 48 h. Administration of GnRHa at any time during the 48 h period of FSH treatment inhibited the subsequent development of gonadotropin and PRL receptors. In contrast, administration of a single dose of 10 micrograms GnRHa after 48 h of FSH treatment stimulated follicular luteinization and caused increases in basal adenylate cyclase activity, ovarian weight and PRL receptor content, and concomitant decreases in gonadotropin receptors and adenylate cyclase responses. In the immature follicles of animals not primed with FSH, GnRHa caused progressive inhibition of FSH-sensitive adenylate cyclase activity, with a decrease in FSH receptors, but increased both basal and GMP-P(NH)P-stimulated adenylate cyclase activities. These results demonstrate that GnRHa causes marked inhibition of gonadotropin receptor expression in the basal and FSH-stimulated ovary. This decrease in gonadotropin receptors is an important component of the mechanism by which GnRH agonists inhibit ovarian gonadotropin-sensitive adenylate cyclase activity. In addition, these peptides exert stimulatory effects upon ovarian weight and basal adenylate cyclase activity, and cause an increase in PRL receptors and luteinization of mature ovarian follicles.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:GnRH agonist-induced inhibitory and stimulatory effects during ovarian follicular maturation. 632 79

The intermediary role of cAMP in the mechanism of action of FSH was reinvestigated in vitro using forskolin, a highly specific adenylate cyclase probe. Granulosa cells from immature hypophysectomized diethylstilbestrol-treated rats were cultured for 3 days in the absence or presence of forskolin. Treatment with increasing concentrations (10(-7)-10(-4) M) of forskolin led to dose-dependent increments in the accumulation of extracellular cAMP, with an apparent median effective dose of 1.6 +/- 0.5 X 10(-5) M. Concomitant blockade of cAMP phosphodiesterase activity further enhanced the forskolin effect. Treatment with forskolin also brought about dose- and time-dependent increments in progesterone and estrogen accumulation. Granulosa cells not pretreated with forskolin displayed negligible LH/hCG binding and remained unresponsive to luteotropic (LH/hCG), beta 2-adrenergic (terbutaline), or lactogenic (PRL) stimulation. In contrast, forskolin (10(-5) M)-pretreated granulosa cells displayed significant increases over controls in LH/hCG binding (46-fold) as well as in progesterone accumulation stimulated by hCG (3.3-fold), terbutaline (1.9-fold), and PRL (1.8-fold). Furthermore, concomitant treatment with a functionally inert low dose (10(-7) M) of forskolin, substantially potentiated the FSH-stimulated accumulation of extracellular cAMP, progesterone, and estrogen as well as the FSH-mediated increase in LH/hCG binding. Taken together, our findings indicate that forskolin, like FSH, is capable of inducing the differentiation of cultured rat granulosa cells by itself, and that a functionally inert low dose of forskolin can potentiate FSH hormonal action. Inasmuch as forskolin-simulated and forskolin-potentiated hormonal action are acceptable as novel criteria of cAMP dependence, our findings provide new evidence in support of the notion that cAMP may be an intracellular second messenger of FSH.
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PMID:Forskolin-induced differentiation of cultured rat granulosa cells: new evidence for an intermediary role of adenosine 3',5'-monophosphate in the mechanism of action of follicle-stimulating hormone. 632 47

An adenylate cyclase present in a PRL-producing tumor cell line, GH1, which is selectively stimulated by chlorpromazine, has been characterized with respect to several biochemical properties. The parameters studied include divalent metal ion specificity, guanyl nucleotide interaction, and sensitivity to sodium fluoride. The effects of calcium and the calcium chelator, EGTA, were also tested on the chlorpromazine response. The data reported herein establish the optimal conditions for the activation of adenylate cyclase by chlorpromazine in homogenates of GH1 cells. In addition, the results from this study identify a heat-stable protein in these cells which regulates cyclase activity. This protein, which can be released into the supernatant by the pretreatment of GH1 cells with EGTA, is an absolute requirement for chlorpromazine stimulation of adenylate cyclase activity in these cells. The activation of adenylate cyclase by chlorpromazine in homogenates of normal rat pituitaries was demonstrated as well as the presence of a protein factor which regulates this activity.
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PMID:Regulation of adenylate cyclase activity in GH1 cells by chlorpromazine and a heat-stable factor. 746 Aug 25

The capacity of brain tumor samples to synthesize pituitary adenylate cyclase activating polypeptide (PACAP) was evaluated by the reverse transcriptase-polymerase chain reaction technique (RT-PCR). The expression of PACAP receptors was assessed by a combination of RT-PCR techniques, conventional binding techniques, and also by the ability of PACAP to stimulate adenylate cyclase activity. A weak PACAP mRNA and PACAP receptor mRNA expression was detected in only 3 of 16 meningiomas. A weak PACAP-stimulated adenylate cyclase activity (+20%) was detected in 10 of the 16 samples but binding of labeled PACAP was never observed. In the 16 gliomas studied (including two oligodendrogliomas and two ependymomas), PACAP mRNA was identified in 13 samples and PACAP receptor mRNA in 15 samples. PACAP receptors were identified in all the samples by binding studies and/or by PACAP stimulation of the adenylate cyclase activity. PACAP mRNA was never detected in pituitary adenomas (three prolactinomas, two mixed PRL-GH-producing tumors, three GH-secreting tumors, three gonadotrophinomas, one ACTH-producing tumor, two nonsecreting tumors) whereas PACAP receptor mRNA was highly expressed in all the tumors except prolactinomas, where it was at the limit of detection, confirming the binding and adenylate cyclase activation results. Thus, it is unlikely that the neuropeptide PACAP could influence meningioma's cell growth; PACAP secreted from extratumoral areas may influence pituitary tumors and PACAP could participate to gliomas development.
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PMID:Expression of pituitary adenylate cyclase activating polypeptide and receptors in human brain tumors. 747 7


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