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)

Binding of catecholamines to the beta-adrenergic receptor results in the activation of adenylate cyclase and the intracellular formation of adenosine 3',5'-monophosphate (cAMP). In the past 20 years the events that lead from hormone binding at the cell surface receptor site to the synthesis of cAMP at the inner layer of the membrane have been intensively studied. Signal transduction in this system involves the sequential interaction of the beta-adrenergic receptor with the guanine nucleotide-binding protein (Gs) and the adenylate cyclase catalyst (C). The mechanism of signal transduction from the receptor through Gs to C, as well as the role of the adenylate cyclase inhibitory G protein Gi, is discussed.
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PMID:From epinephrine to cyclic AMP. 284 58

We have examined the regulation of three early developmentally regulated genes in Dictyostelium. Two of these genes (D2 and M3) are induced by pulses of cAMP and the other (K5) is repressed. Expression of these genes has been examined in a number of developmental mutants that are specifically blocked in various aspects of the signal transduction/cAMP relay system involved in aggregation and control of early development. The mutant strains include Synag mutants, which are blocked in receptor-mediated activation of adenylate cyclase and do not relay cAMP pulses; FrigidA mutants, which are blocked in receptor-mediated activation of both adenylate cyclase and the putative phosphoinositol bisphosphate (PIP2) turnover pathway and appear to be mutations in the gene encoding one of the G alpha protein subunits; and a StreamerF allele, which lacks cGMP-specific cGMP phosphodiesterase. From the analysis of the developmental expression of these genes under a variety of conditions in these mutant strains, we have drawn a number of conclusions concerning the modes of regulation of these genes. Full induction of D2 and M3 genes requires cAMP interaction with the cell surface receptor and an "oscillation" of the receptor between active and adapted forms. Induction of these genes does not require activation of the signal transduction pathway that leads to adenylate cyclase activation and cAMP relay, but does require activation of other receptor-mediated intracellular signal transduction pathways, possibly that involving PIP2 turnover. Likewise, repression of the K5 gene requires pulses of cAMP. Expression of this gene is insensitive to cAMP pulses in FrigidA mutants, suggesting that a signal transduction pathway is necessary for its repression. Results using the StreamerF mutant suggest that the rise in cGMP in response to cAMP/receptor interactions may not be directly related to control of the pulse-induced genes. In addition, we have examined the effect of caffeine, which M. Brenner and S.D. Thomas (1984, Dev. Biol., 101, 136-146) showed preferentially blocks the cAMP relay system by blocking receptor-mediated activation of adenylate cyclase. We show that in many of the mutants and in an axenic wild-type strain, caffeine causes the induction of pulse-induced gene expression to almost wild-type levels or in some cases to higher than wild-type levels. Our data suggest that caffeine works by activating some step in the signal transduction pathway that must lie downstream from both the receptor and at least one of the G proteins and thus has effects other than simply blocking the receptor-mediated cAMP relay system.
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PMID:cAMP regulation of early gene expression in signal transduction mutants of Dictyostelium. 284 88

Vasoactive intestinal peptide (VIP) is a neuropeptide with a broad range of biological activities in various tissues. After interaction with its membrane receptor, VIP generally induces a very large increase in the intracellular cyclic AMP level. Receptors for VIP have been described in numerous tissues and cell lines. The first results on VIP receptor structure have been obtained by covalent cross-linking using bifunctional reagents. The molecular mass of the different components characterized in this way differs greatly according to the species and the tissue used. This heterogeneity may reflect either a difference in the length of the cross-linked polypeptide backbone or differently glycosylated forms of the same polypeptide. The VIP binding site of intact human adenocarcinoma cells (HT29 cells) is an Mr 64,000 glycoprotein with 20kDa of N-linked oligosaccharide side chains containing sialic acid. The structure of the VIP binding site from HT29 cell is compared, first to the structure of the VIP receptor from other tissues, particularly that from rat liver, and second to the structure of the hepatic glucagon binding site. Recently, solubilization of the VIP receptor in an active form has provided a new way of studying this receptor. The HT29 cell line is an appropriate model to study the dynamics of the VIP receptor. After binding to its receptor, VIP is rapidly internalized, probably by receptor-mediated endocytosis. This internalization leads to a decrease in the cell surface receptor number and simultaneously to a homologous desensitization of adenylate cyclase. VIP is then degraded in the lysosomes, while most of the receptors are recycled back to the cell surface. The presence of an intracellular pool of unoccupied VIP receptors has been demonstrated after inactivation of the cell surface receptors by chymotrypsin. The kinetics of the receptor reappearance at the cell surface, after inactivation by chymotrypsin or after receptor-mediated endocytosis, indicate 2 possible intracellular pathways for occupied and unoccupied VIP receptors.
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PMID:The vasoactive intestinal peptide (VIP) receptor: recent data and hypothesis. 285 63

Elevated levels of cAMP are essential for the expression of many postaggregation prespore and prestalk mRNA species and for the suppression of some growth phase mRNAs. Here we review evidence that this regulation is mediated by cAMP interacting at the cell surface receptor. These effects of cAMP on gene expression can occur under conditions where the receptor-associated adenylate cyclase is inactivated and in concentrations that are consistent with receptor-binding. A number of differences are noted in the mechanism by which cAMP regulates prespore and prestalk genes. Finally, evidence is reviewed for the role of a Ca2+-dependent signal transduction system in coupling the expression of some of the prespore mRNAs to the cAMP receptor. This signal transduction system does not appear to be involved in the expression of the cAMP-dependent prestalk gene.
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PMID:A Ca2+-dependent signal transduction system participates in coupling expression of some cAMP-dependent prespore genes to the cell surface receptor. 285 23

It is very well established that the principal control of salivary secretion is derived from autonomic innervation. Transmission of a neural signal to a salivary gland acinar cell occurs chemically via neurotransmitters, the first messengers of a secretory response. Neurotransmitters bind to specific cell surface receptor proteins, an event which activates precise transduction mechanisms which then transfer the neural signal to the inside of the cell. There are two major transduction mechanisms operative in salivary gland acinar cells. One involves the generation of cAMP, the other involves the breakdown of plasma membrane polyphosphoinositides. For both mechanisms, the appropriate stimulated receptor activates a second plasma membrane protein, termed an N (or G) protein. The N protein requires GTP to activate an enzyme (adenylate cyclase or phospholipase C), which then catalyzes the formation of a second messenger (cAMP and inositol trisphosphate/diacylglycerol, respectively). This action provides the intracellular signal for secretory events (protein, fluid, electrolyte secretion) to begin.
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PMID:Neurotransmitter control of secretion. 288 3

Cholesterol, a major structural component of plasma membranes, has a profound influence on cell surface receptor characteristics and on adenylate cyclase activity. beta-Adrenergic receptor number, adenylate cyclase activity, and receptor-cyclase coupling were assessed in rat lung membranes following preincubation with cholesteryl hemisuccinate. beta-Adrenergic receptor number increased by 50% without a change in antagonist affinity. However, beta-adrenergic receptor affinity for isoproterenol increased 2-fold as a result of an increase in the affinity of the isoproterenol high-affinity binding site. The increase in agonist affinity did not potentiate hormone-stimulated adenylate cyclase activity, which decreased 3-fold following cholesterol incorporation. However, the ratio of isoproterenol to GTP-stimulated activity was unchanged with cholesterol. Stimulation distal to the receptor by GTP, NaF, GppNHp, Mn2+ and forskolin also demonstrated 50-80% reduced enzyme activity following cholesterol incorporation. These data suggest that membrane cholesterol incorporation decreases catalytic unit activity without affecting transduction of the hormone signal.
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PMID:Cholesterol modulation of beta-adrenergic receptor characteristics. 298 44

Adenosine and prostaglandins (PGs) are known inhibitors of oxyntic cell function. Using quantitative cytochemistry of hydroxyl ion production (HIP) in guinea-pig oxyntic cells, we examined the effects of adenosine and PGs on secretagogue-stimulated HIP. Adenosine (10(-6) M) inhibited the actions of histamine (10(-14) M) and gastrin (2.5 X 10(-12) M) by 69 and 67%, respectively, but not that of dibutyryl cyclic AMP (10(-16) M) or carbachol (10(-9) M). These observations suggest that adenosine does not influence the Ca++-dependent pathway of carbachol action and that the adenosine activity precedes the generation of cyclic AMP. Adenosine and related analogs, N6-L-phenylisopropyladenosine and 5-N-ethylcarboxam-idoadenosine (10(-12) to 10(-14) M), inhibited histamine-stimulated HIP (10(-14) M) in the following order: N6-L-phenylisopropyladenosine greater than 5-N-ethylcarboxamidoadenosine greater than adenosin. The adenosine antagonist, 1,3-diethylphenylxanthine (10(-6) M), reversed the inhibitory effects of adenosine. Exogenous PGE2 (10(-6) M) also inhibited histamine- and gastrin-stimulated HIP by 65 and 55%, respectively. Indomethacin (10(-6) M) and flurbiprofen (10(-6) M), PG synthesis inhibitors, potentiated the action of histamine by 175 and 159%, respectively. Adenosine was incapable of reversing this potentiated effect. These data indicate that adenosine and related analogs are inhibitors of oxyntic cell HIP and suggest that these biological properties are mediated by binding to a cell surface receptor and thereby regulating oxyntic cell adenylate cyclase activity. The more potent properties of N6-L-phenylisopropyladenosine as compared to 5-N-ethylcarboxamidoadenosine are consistent with activity at the high-affinity surface adenosine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of guinea-pig oxyntic cell function by adenosine and prostaglandins. 300 79

A previous report demonstrated both immunological crossreactivity and structural similarity between the mammalian beta adrenergic receptor and the cell surface receptor for the reovirus type 3 (14). We now demonstrate that reovirus type 3 can bind selectively and with high affinity to cells that lack beta adrenergic receptor activity (L-cells). The present study was also designed to determine what effect reovirus binding has on beta adrenergic receptor function in cells (DDT1) that possess an intact ligand binding site. Based on computer analysis of reovirus competitive inhibition curves, the apparent dissociation binding constants (Kd) for reovirus binding to DDT1 and L-cells are 0.1 nM and 0.25 nM, respectively. High affinity [125I]-iodocyanopindolol (CYP) binding to beta adrenergic receptors can also be demonstrated in DDT1 cells but not in L-cells. In agreement with these ligand binding studies, adenylate cyclase activity is stimulated by the beta receptor agonist isoproterenol in DDT1 cell membranes but not in L-cell membranes. In addition, isoproterenol increases cAMP levels in DDT1 cells but not in L-cells. Neither reovirus serotype stimulates cAMP levels in either cell line, nor do they influence beta-adrenergic agonist stimulation of cAMP in DDT1 cells. These results argue against identity of the receptors for reovirus type 3 and beta adrenergic ligands.
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PMID:High affinity binding of reovirus type 3 to cells that lack beta adrenergic receptor activity. 302 84

We have previously shown that in rat H4 hepatoma cells insulin enhances the nuclear transcription of p33 mRNA in a dose- and time-dependent manner, with no alteration in mRNA half-time (t1/2). Presumably, this effect is mediated by the cell surface receptor. In this report, we have investigated the effect of putative insulin mediator fractions which act to control metabolic events on p33 mRNA accumulation in these cells. Initial experiments originally demonstrated an insulin-like effect of an added putative metabolic fraction to enhance p33 mRNA concentrations. However, when the fetal calf serum supply was changed, the effect of insulin remained, but that of added mediator was no longer observed. After a series of experimental approaches designed to alter the permeability of the cell membrane, it was found that in the presence of increased Ca2+, the effect of mediator could again be observed. The present data demonstrate that the partially purified cAMP-dependent protein kinase/adenylate cyclase inhibitory putative mediator fractions from liver and muscle enhance p33 mRNA accumulation in intact H4 hepatoma cells by a mechanism that is differentiated from that of insulin. The action of the putative mediator is inhibited by cycloheximide, while the action of insulin itself is not. These results suggest that insulin may control nuclear transcription by multiple signaling mechanisms. Alternatively, the added putative metabolic mediator may not enter the cell in the presence of cycloheximide or is inactive as such within the cell and must first be converted to an active species by a step requiring protein synthesis.
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PMID:Insulin and a putative insulin metabolic mediator fraction from liver and muscle stimulate p33 messenger ribonucleic acid accumulation by apparently different mechanisms. 304 71

Prostaglandins inhibit the proliferation of the murine P815 mastocytoma. The mechanism of this antitumour activity remains undefined. In several cell systems, the action of PGs is inhibited at the cell surface receptor by pertussis toxin likely through regulatory G proteins involved in the inhibition of adenyl cyclase or activation of phospholipase C. We therefore determined the effect of prostaglandins on the biochemical consequences of activation of these pathways; i.e. concentrations of cyclic AMP (cAMP) and cytosolic free Ca+2 concentrations [( Ca/2]i) respectively. PGD2 (6 ug/mL), PGE1 (10 ug/mL) and PGB1 (50 ug/mL) maximally inhibited (3H)-thymidine incorporation to DNA. PGF2 alpha did not affect DNA synthesis. PGE1 (10 ug/mL) induced a three fold increase in cAMP concentrations. In contrast, the other prostaglandins did not alter cAMP concentrations. Maximal growth inhibitory doses of PGD2, PGE1 and PGB1 decrease [Ca+2]i, as measured by the fluorescence of Indo-1, from 320 +/- 5 nM to 172 +/- 20 nM, 161 +/- 12 nM, and 151 +/- 18 nM respectively. PGF2 alpha did not alter [Ca+2]i. Therefore, in contrast to the effects on cAMP, the decrease in [Ca+2]i was concordant with the inhibition of DNA synthesis. This suggests that PGs may inhibit proliferation through decreasing [Ca+2]i in the P815 mastocytoma.
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PMID:Prostaglandins inhibit proliferation of the murine P815 mastocytoma by decreasing cytoplasmic free calcium levels [( Ca+2]i). 314 77


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