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)

1. Membrane currents were recorded from voltage clamped Xenopus laevis oocytes, still surrounded by follicular cells, theca and enveloping inner ovarian epithelia (ovarian follicles). 2. Superfusing follicles with frog Ringer solution containing E-series prostaglandins (PGE1 or PGE2) or oxytocin (0.5-2 microM) generated slow membrane currents arising from an increase in membrane conductance to K+. 3. Follicles taken from different frogs varied greatly in responsiveness to PGE and oxytocin. For example, enclosed oocytes with good sensitivity to prostaglandins responded to 1 nM-PGE, whereas follicles from some frogs failed to respond at 5 microM. 4. Oocytes with good responsiveness to PGE also produced K+ currents to PGA1, PGA2, PGB1, 11-deoxy-PGE1 and 11-beta-PGE2, whereas PGF2 alpha, PGI2, PGD2 and 8-iso-PGE1 generally failed to elicit membrane currents. 5. Responses to PGE and oxytocin were mimicked by the adenylate cyclase activator forskolin or by intraoocyte pressure injection of cyclic nucleotides. Responses were potentiated by the phosphodiesterase inhibitors theophylline and 3-isobutyl-1-methylxanthine (IBMX). In IBMX (0.5 mM), human atrial natriuretic factor (ANF) (10-60 nM) elicited a similar K+ conductance. This all implied that cyclic nucleotides played a role in the receptor-channel coupling mechanism of these responses. 6. Defolliculating oocytes effectively abolished responses to prostaglandins, oxytocin and ANF, suggesting that the currents arise in follicular cells. 7. The responses of PGE, oxytocin and ANF thus resembled currents elicited by catecholamines, adenosine, gonadotrophins and vasoactive intestinal peptide (VIP). However, PGE, oxytocin and ANF responses were not blocked by catecholaminergic or purinergic antagonists. Moreover, when comparing follicles isolated from different frogs, the sensitivity to PGE and oxytocin varied independently of that to gonadotrophin or VIP. These experiments suggest that Xenopus ovarian follicles contain specific and distinct receptors for PGE, oxytocin and ANF. 8. Acetylcholine attenuated the cyclic nucleotide-mediated K+ responses, including currents elicited by PGE, oxytocin and ANF. Attenuation was not dependent on, or mimicked by, activation of the inositol phosphate-diacylglycerol messenger pathways located in the oocyte itself, nor was it appreciably blocked by loading follicle-enclosed oocytes with 0.1-1.5 mM-EGTA.
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PMID:Membrane currents elicited by prostaglandins, atrial natriuretic factor and oxytocin in follicle-enclosed Xenopus oocytes. 248 34

The effect of chronic estrogen treatment on the anterior pituitary D2 dopamine receptor was studied by treating rats with diethylstilbestrol (DES) over a 6-week period. DES treatment resulted in an increase in anterior pituitary weight and PRL content and serum PRL levels compared to those in sham-treated controls. The status of the anterior pituitary D2 dopamine receptor was evaluated using both radioligand binding and adenylate cyclase assays. [125I]N-(p-aminophenethyl)spiroperidol [( 125I]NAPS), a derivative of the D2-selective antagonist spiperone, was used to quantitate D2 receptors. Saturation analysis of [125I]NAPS binding indicated that DES treatment had no effect on the affinity or maximum binding capacity of the radioligand for the D2 receptor. Competition analysis with unlabeled D2 antagonists for [125I]NAPS binding also indicated that DES treatment did not affect antagonist interactions with the receptor. In contrast, the interactions of agonists with the D2 receptors from DES-treated rats were modified, as assessed through [125I]NAPS competition analysis. Using control tissue, agonist competition curves revealed both high and low affinity agonist binding states of the receptor. In the presence of guanine nucleotides, the high affinity agonist binding state is abolished, reflecting coupling of the receptor with a guanine nucleotide regulatory (G) protein. In DES-treated tissue, agonist competition curves indicated the presence of only low affinity agonist binding, with minimal effects of guanine nucleotides, suggesting uncoupling of receptor-G-protein interactions. The functionality of the D2 receptor was further assessed by examining dopaminergic inhibition of vasoactive intestinal peptide-stimulated adenylate cyclase activity. Although DES treatment resulted in a reduction of vasoactive intestinal peptide-stimulated enzyme activity itself, the ability of dopaminergic agonists to inhibit this activity was reduced by about 50%. These results suggest that estrogen is capable of attenuating the functional coupling of the D2 receptor with its biochemical effector system in the anterior pituitary gland.
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PMID:Chronic estrogen treatment promotes a functional uncoupling of the D2 dopamine receptor in rat anterior pituitary gland. 252 Dec 6

A polarized human clonal intestinal cell line exhibiting mucus secretion (Cl.16E) was used to study the expression and function of vasoactive intestinal peptide (VIP) receptors in mucus-secreting cells. Cl.16E cells expressed one class of receptors with a KD of 0.13 nM and a capacity of 67 fmol/mg protein. Covalent labeling of receptors followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a receptor protein with a Mr of 63,000 in Cl.16E cells. VIP stimulated adenylate cyclase activity in membranes from Cl.16E cells with an ED50 of 0.06 nM. In conditions where carbachol stimulated mucin secretion from filter-grown Cl.16E cells, VIP, dibutyryl adenosine 3',5'-cyclic monophosphate (DbcAMP), or forskolin did not alter basal secretion. However, VIP strongly potentiated carbachol-induced mucin secretion, since carbachol alone and VIP plus carbachol induced a 1.6- and 3.6-fold increase of mucin secretion above basal, respectively. This potentiating effect of VIP was mimicked by DbcAMP or forskolin. It was observed for VIP concentrations in the 0.1-100 nM range (ED50, 2 nM). VIP elicited a dramatic increase of intracellular cAMP levels in filter-grown Cl.16E cells with a dose-response curve (ED50, 4 nM) very similar to that observed for the modulation of mucin secretion. These studies suggest that the clonal cell line Cl.16E may be an invaluable cellular model for evaluating the neurohormonal control of mucus secretion.
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PMID:Functional VIP receptors in the human mucus-secreting colonic epithelial cell line CL.16E. 253 74

Previous work has shown that corticotropin releasing factor, vasoactive intestinal peptide, phorbol ester, and forskolin cause the secretion of adrenocorticotropic hormone and beta-endorphin from the AtT-20 mouse pituitary cell line. Human recombinant interleukin 1 alpha and 1 beta also stimulated adrenocorticotropic hormone and beta-endorphin secretion from AtT-20 cells in a time- and dose-related manner. The effect appeared only after pretreatment with interleukin 1 (IL-1) for at least 18 hr and was maximum at 24 hr. After pretreatment of the cells over a period of time with IL-1, the secretion induced by corticotropin releasing factor and vasoactive intestinal peptide was increased in more than an additive manner. The enhancement of corticotropin releasing factor-induced beta-endorphin release produced by IL-1 was apparent after 12 hr and reached a maximum at 24 hr. IL-1 did not affect forskolin-induced cAMP generation but enhanced the effect of forskolin on beta-endorphin secretion. This suggests that IL-1 does not induce adenylate cyclase and that forskolin causes the secretion of beta-endorphin by a mechanism independent of cAMP. IL-1 enhanced phorbol ester-induced beta-endorphin secretion. After prolonged treatment with phorbol ester (an activator of protein kinase C), the secretion induced by phorbol ester was abolished as well as the enhancement induced by IL-1. However, prolonged treatment with phorbol ester had no effect on IL-1-induced beta-endorphin secretion. These observations suggest that IL-1 enhances peptide-generated secretion of beta-endorphin by inducing protein kinase C.
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PMID:Interleukin 1 potentiates the secretion of beta-endorphin induced by secretagogues in a mouse pituitary cell line (AtT-20). 253 29

Specific, high affinity receptors for vasoactive intestinal peptide (VIP) have been identified on a human pre-B cell line, Nalm 6, and on a human plasma cell line, Dakiki. The single class of high affinity sites exhibited a KD of 12.6 +/- 2.9 nM for VIP in Nalm 6 cells and 9.1 +/- 2.7 nM in Dakiki plasma cells. The homologous peptides, peptide histidine methionine (PHM), growth hormone releasing factor (GHRF), and secretin were all less effective than VIP in competitively inhibiting binding of 125I-VIP to Nalm 6 and Dakiki plasma membranes. The putative receptor was characterized as a 47-kDa protein using covalent cross-linking techniques and VIP stimulated adenylate cyclase in pre-B cells. Human lymphocytes of B cell lineage thus appear to express functional VIP receptors homologous to the receptor identified in T lymphoblasts, brain, pituitary, and intestine.
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PMID:Identification of high affinity receptors for vasoactive intestinal peptide on human lymphocytes of B cell lineage. 254 Nov 99

The present experiments examined the effects of progesterone on adrenergic receptor coupling to adenylate cyclase in hypothalamic and preoptic area slices by monitoring norepinephrine (NE)-stimulated increases in cAMP accumulation. Progesterone treatment of estrogen-primed rats decreased NE-induced slice cAMP accumulation. The reduced cAMP response was estrogen-dependent since it was not demonstrable in slices from rats exposed to progesterone without prior estrogen priming. Neither generalized increases in phosphodiesterase activity nor decreases in the catalytic activity of adenylate cyclase could account for the reduced ability of NE to stimulate cAMP accumulation in hypothalamic slices. Moreover, the cAMP response to two other activators of adenylate cyclase, adenosine and vasoactive intestinal peptide, was not decreased in slices from rats treated with estrogen plus progesterone. Selective adrenergic agonists and antagonists were employed to determine which adrenergic receptors mediate cAMP accumulation in progesterone-exposed slices. Slice cAMP levels were elevated by the beta receptor agonist isoproterenol but not by alpha 1 (phenylephrine) or alpha 2 (clonidine) agonists. However, clonidine potentiated the effect of isoproterenol on slice cAMP formation whereas phenylephrine did not. Likewise, NE-stimulated cAMP accumulation was completely antagonized only by a combination of both beta (propranolol) and alpha 2 (yohimbine) antagonists. The data suggest that in slices from estrogen plus progesterone-treated rats, alpha 2 receptors contribute significantly to NE stimulation of cAMP accumulation. The overall depression of the cAMP response to NE in progesterone-exposed slices may involve a decrease of alpha 1 receptor facilitation of cAMP synthesis.
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PMID:Progesterone depression of norepinephrine-stimulated cAMP accumulation in hypothalamic slices. 254 2

Properties of a clonal line of SV40-transformed rat granulosa cells (DC3 cells) were elucidated. DC3 cells were maintained in vitro in Iscove Modified Dulbecco Medium that contained 20% fetal bovine serum. The cells had a logarithmic growth phase doubling time of approximately 18 h and produced detectable quantities of estrone, estradiol, and progesterone. Steroidogenesis was increased by supplementation with either steroidogenic substrates or agents that stimulated activity of adenylate cyclase. Production of progesterone and estrogens was enhanced when medium was supplemented with 25-hydroxycholesterol, and production of estradiol was enhanced by medium supplementation with androstenedione. Treatments with forskolin and cholera toxin resulted in marked increases of cyclic adenosine 3',5'-monophosphate (cAMP) in medium and cells and enhanced steroidogenesis. Isoproterenol and vasoactive intestinal peptide, but not follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin or prolactin, stimulated cAMP secretion by suspended cells. DC3 cells had small but detectable levels of binding to FSH, but binding of LH and epidermal growth factor could not be detected. DC3 cells possess characteristics expected of granulosa cells arrested in an early stage of differentiation and may provide a useful model for studies of "immature" granulosa cell functions.
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PMID:Physiologic characterization of transformed and cloned rat granulosa cells. 254 13

Certain neuropeptides, including vasoactive intestinal peptide, inhibit peptidoleukotriene release from platelet activating factor-stimulated rat lung. We have now shown that vasoactive intestinal peptide will also inhibit peptidoleukotriene release from platelet activating factor-stimulated or ovalbumin-challenged guinea pig lung, but not from calcium ionophore-stimulated rat or guinea pig lung. In rat lung a pre-incubation with the peptide prior to addition of platelet activating factor was required for the effect to be maximal. When vasoactive intestinal peptide was substituted with cyclic AMP, the inhibitory effect was reproduced. In addition, pre-incubation with MDL 12330A, an inhibitor of adenylate cyclase, reduced the inhibitory effect of vasoactive intestinal peptide on platelet activating factor-stimulated leukotriene C4 biosynthesis. We suggest that the inhibition of platelet activating factor-stimulated peptidoleukotriene release in rat lung by vasoactive intestinal peptide involves the events prior to phospholipase A2 activation and requires cyclic AMP as a mediator.
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PMID:The role of cyclic AMP in the inhibition of leukotriene biosynthesis by neuropeptides. 254 50

The effect of amiloride on the hormonal regulation of adenylate cyclase was studied in the rat anterior pituitary. The diuretic did not alter basal adenylate cyclase but augmented the enzyme activity in an irreversible manner in the presence of guanosine 5'-O-(thiotriphosphate) (GTP gamma S) stimulated adenylate cyclase at lower concentrations and inhibited at higher concentrations. Amiloride treatment enhanced the stimulatory and abolished the inhibitory phase of GTP gamma S action. In addition, amiloride also attenuated the inhibitory effects of atrial natriuretic factor (ANF 99-126) and angiotensin II on cAMP levels and adenylate cyclase activity. On the other hand, amiloride showed an additive effect on the stimulation exerted by corticotropin-releasing factor and vasoactive intestinal peptide on adenylate cyclase in anterior pituitary and on isoproterenol-stimulated cAMP levels in cultured vascular smooth muscle cells. Pertussis toxin, in the presence of [alpha-32 P]NAD, catalyzed the ADP-ribosylation of two protein bands of Mr 41,000 and 39,000, referred to as Gi and Go, respectively, in the anterior pituitary, and 40,000-Da protein in the aorta, referred to as Gi. Amiloride treatment inhibited the labeling of all these bands in a concentration- and time-dependent manner. Similarly, the pertussis toxin-catalyzed ADP-ribosylation of purified Gi from bovine brain was also inhibited by amiloride treatment. However, amiloride had no significant effect on the cholera toxin-catalyzed ADP-ribosylation of Gs. These data suggest that amiloride interacts with the guanine nucleotide regulatory proteins Gi and Go. Modification of Gi results in the attenuation of hormone-induced adenylate cyclase and cAMP inhibition. However, the interaction between amiloride and Go and the consequent Ca2+ mobilization and phosphatidylinositol turnover have to be investigated.
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PMID:Amiloride interacts with guanine nucleotide regulatory proteins and attenuates the hormonal inhibition of adenylate cyclase. 254 11

Muscarinic receptor stimulation increased the accumulation of 3H-inositol phosphates in PC12 cells whose phospholipids had been prelabeled with [3H]inositol. Muscarine also inhibited the increase in cyclic AMP (cAMP) accumulation caused by 5'-N-ethylcarboxamide adenosine or by vasoactive intestinal peptide. This effect of muscarine was apparently due to the inhibition of adenylate cyclase rather than to a stimulation of a cAMP specific phosphodiesterase. The muscarinic receptor antagonist pirenzepine inhibited both the stimulation of inositol-phospholipid metabolism and the inhibition of cAMP production with Ki values of 0.34 microM and 0.36 microM, respectively. PC12 cells contained a single class of N-[3H]methylscopolamine ([3H]NMS) binding sites. Competition studies with muscarine (KD, 15 microM) and pirenzepine (Ki, 0.12 microM) revealed no evidence for multiple muscarinic receptors. The Ki of pirenzepine for the inhibition of [3H]NMS binding and the inhibition of muscarinic actions is consistent with the possibility that this is not an M1 receptor. Muscarine inhibited cAMP accumulation in cells made deficient in protein kinase C; therefore, this protein kinase is probably not involved in mediating the inhibitory effect of muscarine. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate also inhibited cAMP accumulation in PC12 cells but the mechanism of this effect differed from that of muscarine. Bradykinin caused a large increase in the accumulation of 3H-inositol phosphates and [3H]diacylglycerol relative to muscarine but did not inhibit cAMP production. Oxotremorine inhibited cAMP accumulation but it did not stimulate inositol-phospholipid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic receptor stimulation increases inositol-phospholipid metabolism and inhibits cyclic AMP accumulation in PC12 cells. 254 58


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