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)

Sugars such as glucose are transported into Escherichia coli by a coupled phosphorylation mechanism (the phosphoenolpyruvate:sugar phosphotransferase system, PTS). Transport of sugars through the PTS results in inhibition of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity by a mechanism involving a change in the state of phosphorylation of PTS proteins. Other sugars (e.g., lactose) are transported without modification by a mechanism involving proton cotransport, which requires a proton motive force across the cell membrane. We show here that uptake of sugars through the lactose transport system results in inhibition of adenylate cyclase activity if the proton symport mechanism is also active. The protonophore carbonyl cyanide m-chlorophenylhydrazone also inhibits adenylate cyclase activity. These data suggest that the steady-state electrochemical proton gradient regulates the activity of adenylate cyclase. We propose that sugar-dependent inhibition of adenylate cyclase activity may occur by either of two mechanisms. Sugars transported by the PTS inhibited adenylate cyclase activity by dephosphorylation of a regulatory protein, while sugars transported by the proton motive force system inhibit adenylate cyclase activity as a result of collapse of the proton electrochemical gradient.
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PMID:Escherichia coli adenylate cyclase complex: regulation by the proton electrochemical gradient. 10 76

Rat mammary (Rama 25) and dog kidney (MDCK) epithelial cell cultures formed 'domes' of cells due to fluid accumulation in focal regions between the culture dish and the cell monolayer. Addition of ouabain caused collapse of domes, suggesting that transport functions were required for maintenance of domes. Dome formation in both epithelial cell lines was stimulated by a broad spectrum of known inducers of erythroid differentiation in Fried erythroleukemia cells. Among these inducers were: 1) polar solvents such as dimethyl-sulfoxide, dimethylformamide, and hexamethylene bisacetamide; 2) purines such as hypoxanthine, inosine, and adenosine; 3) low-molecular-weight fatty acids such as n-butyrate; and 4) conditions expected to elevate levels of cyclic AMP. In the latter group were activators of adenylate cyclase such as cholera toxin and prostaglandin E 1; cyclic AMP phosphodiesterase inhibitors such as theophylline and 1-methyl-3-isobutylxanthine; and analogs of cyclic AMP. Induction of domes occurred 15--30 h after addition of inducer to the culture medium. Induction by chemicals was serum-dependent and required protein synthesis but not DNA synthesis. Induced dome formation was reversible after removal of inducer, requiring the continuous presence of inducer. Reversal was also observed after either either removal of serum or addition of inhibitors of protein synthesis. These results suggest that hypothesis that domes arise in these epithelial cultures by a process that is similar to cell differentiation and is influenced by cyclic AMP.
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PMID:Regulation of dome formation in differentiated epithelial cell cultures. 23 29

It is hypothesized that (cAMP, ATP) is the elusive, universal Turing morphogenetic couple, which defies the second law of thermodynamics, i.e. the inexorable march towards homogeneity. cAMP and ATP can be distributed nonhomogeneously because the whole of the intermediary metabolism is so organized that they mutually satisfy the Turing bifurcation conditions upon nonlocalized application of an extracellular ligand, in particular a soluble peptide growth factor, which is nature's distinguished universal bifurcation parameter, acting homogeneously in space and removing the substrate inhibition from adenylate cyclase and thus triggering embryonic induction by triggering the (cAMP, ATP) Turing system. The hypothesis predicts that although the extracellular signal, the growth factor, is applied homogeneously, an organized "dissipative structure" will emerge spontaneously in the responding tissue; this "symmetry breaking" in a reaction-diffusion system occurs precisely in the manner envisaged by Turing, where (cAMP, ATP) constitutes the "reaction-diffusion system". This Turing bifurcation explicates the recent experiments where a differentiated embryoid emerges from the mere immersion of frog animal caps in an homogeneous growth factor solution, and similar experiments on chicks. The "metabolic" patterns found by Child and colleagues also reflect dissipative structures arising in a (cAMP, ATP) reaction-diffusion system when interpreted in the light of modern biochemistry: in particular, the localized glycogen depletion reflects localized cAMP; localized redox, respiratory or susceptibility activity reflects localized ATP. The dramatic collapse of organized structure found by Child and colleagues, for example, when Planaria or a section of it is exposed to an homogeneous environment of a narcotic solution, and the reemergence of structure upon return to water, are explained on the basis of the violation or satisfaction of the Turing bifurcation conditions with respect to (cAMP, ATP), respectively. cAMP is the "activator", ATP is the "inhibitor", and together they mutually satisfy the four activator-inhibitor inequalities, including the all-important autocatalytic cAMP production, as well as the lateral inhibition condition. The functional significance of gap junctions is to generate a multicellular purely reaction-diffusion system for (cAMP, ATP) as envisaged by Turing. It is emphasized that localization and pattern formation occur intracellularly in gap junction-coupled cells and not, as often suggested, extracellularly, the latter localization being too fragile to be maintained for long enough, and soon succumbing to the mixing effect of convection and movement. The activator-inhibitor property of (cAMP, ATP) means that the spatial distribution of cAMP and ATP could be not only nonhomogeneous but also of the same shape.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An hypothesis: phosphorylation fields as the source of positional information and cell differentiation--(cAMP, ATP) as the universal morphogenetic Turing couple. 165 48

To determine a renal tubular mechanism for the natriuretic effect of dopamine (DA) and DA-1 agonists, we measured Na(+)-H+ exchange activity (amiloride sensitive) in rat renal cortical brush-border membrane vesicles (BBMV). Renal cortical tissues were preincubated with ligands before BBMV preparation to study Na(+)-H+ exchange activity in the absence of the added ligands that may compete for ion binding sites of the exchanger. DA and DA-1 agonist-inhibited Na(+)-H+ exchange activity was concentration and time dependent. The inhibitory effect was not due to increased permeability, collapse of the proton gradient, or change in vesicle size and did not extend to Na(+)-glucose symport. DA-2 agonists had no effect, whereas alpha-adrenergic agonists increased Na(+)-H+ exchange activity. Kinetic analysis revealed that the DA-1 agonist inhibited Na(+)-H+ exchange activity by a noncompetitive process. 2',5'-Dideoxyadenosine inhibited adenylate cyclase activity and reversed the inhibitory effect of DA-1 agonist on the exchanger. H4, an isoquinoline sulfonamide, which inhibits protein kinase A, also reversed the inhibitory effect of DA-1 agonist on the exchanger. Thus the DA-1 agonist-mediated inhibition of Na(+)-H+ exchange activity in BBMV is a receptor-mediated adenylate cyclase-linked process.
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PMID:Dopamine inhibits Na(+)-H+ exchanger activity in renal BBMV by stimulation of adenylate cyclase. 197 37

The results presented here demonstrate that an elevation in the cellular levels of cyclic AMP (cAMP) increases the phosphorylation of an Mr = 58,000 cellular protein in quiescent cultures of Swiss 3T3 cells. The enhancement of 32Pi incorporation into the Mr 58,000 cellular protein was detected as early as 1 min and reached a maximum after 20 min of treatment. The role of cAMP in the phosphorylation of Mr = 58,000 protein is substantiated by the following lines of evidence: a) a variety of agents that cause cAMP accumulation in 3T3 cells, including cholera toxin, 5'-N-ethylcarboxamideadenosine (NECA), PGE1, and 3-isobutyl-1-methyl-xanthine (IBMX) increased the phosphorylation of the same Mr 58,000 cellular protein as demonstrated by peptide mapping; b) inhibitors of cyclic nucleotide phosphodiesterase potentiated the ability of low concentrations of the adenylate cyclase activators NECA, PGE1, and forskolin to increase Mr 58,000 phosphorylation; and c) permeable derivatives of cAMP such as 8BrcAMP were also effective and specific in promoting Mr 58,000 phosphorylation. Detergent extraction, immunoblotting, and immunoprecipitation identified the Mr = 58,000 phosphoprotein as vimentin, the main protein subunit of the intermediate filaments of mesenchymal cells including Swiss 3T3 cells. Studies with intact 3T3 cells revealed that an increase in the intracellular level of cAMP induced a marked redistribution and collapse of the intermediate filaments. These results raise the possibility that an intact intermediate filament network may restrict the reinitiation of DNA synthesis.
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PMID:Cyclic AMP increasing agents rapidly stimulate vimentin phosphorylation in quiescent cultures of Swiss 3T3 cells. 246 73

Lysophosphatidic acid (LPA) is a mitogenic phospholipid produced by certain activated cells and present in serum. LPA stimulates phospholipase C and inhibits adenylate cyclase in its target cells, apparently by activating a specific G-protein-coupled receptor. Here, we demonstrate that LPA causes transient rounding of N1E-115 and NG108-15 neuronal cells accompanied by growth cone collapse and retraction of neurites. The effect of LPA is concentration dependent, being half-maximal at 10-20 nM, and reversibly blocked by suramin, an LPA receptor antagonist. The morphological response to LPA is indistinguishable from that evoked by thrombin or a thrombin receptor-activating peptide (TRP) (K. Jalink and W. H. Moolenaar, J. Cell Biol., 118: 411-419, 1992); yet, LPA and thrombin appear to act through distinct receptors. LPA-induced shape changes, like those induced by thrombin and TRP, are driven by contraction of the cortical actin cytoskeleton and not attributable to prior phospholipid hydrolysis and Ca2+ mobilization nor to other classic second messenger systems. Instead, LPA- and TRP-induced shape changes are accompanied by a small but significant increase in p60src protein tyrosine kinase activity. Treatment of cells with pervanadate selectively inhibits LPA- and TRP-induced shape changes as well as p60src activation. These results indicate that, in N1E-115 and NG108-15 cells, LPA and TRP trigger neurite retraction and cell rounding through a novel, receptor-mediated signaling pathway, and they suggest that p60src may play a role in this pathway.
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PMID:Lysophosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action. 768 47

The effects of parathyroid hormone (PTH) on 1,4,5-inositol triphosphate (1,4,5-IP3) and intracellular free calcium (Cai2+) in osteoblasts are variable, whereas adenylate cyclase activity is consistently stimulated. Cyclic AMP is considered a mediator in the contractile effects of PTH on osteoblasts, but the regulation and role of Cai2+ remains unclear. Recent studies indicate that protein kinase C (PKC) inhibits PTH-stimulated Cai2+ increases in osteoblastic cells. Therefore, the objectives of this study were to determine the effects of PKC modulators and PTH on UMR 106-H5 rat osteoblastic cell morphology, and the relationship between cell shape and PTH-induced Cai2+ changes. In suspended cells loaded with the calcium indicator dye fura-2, pretreatment with PKC inhibitors calphostin C (100 nM x 1 h) and H-7 (30 microM x 18 h) potentiated the effects of 1 microgram/ml bPTH (1-84) on Cai2+ (83% increase over basal) by 1.4- and 1.65-fold, respectively. In comparison, PTH (10 ng-1 micrograms/ml) was without significant effect on adherent cell Cai2+ as measured by single-cell image analysis, although another in vitro bone resorbing agent, thrombin (10 U/ml), produced an acute 3-fold increase in the ratio (R) of emission (approximately lambda 510 nm) detected and optimized at lambda 348/374 nm (i.e., Ca-bound dye/free dye) in control cells. Phase-contrast microscopy revealed PKC inhibitor-treated cells changed from a spread configuration to a stellate form with retracting processes or cell rounding and a collapse of actin stress fibers. Within 1 h of PTH addition, PKC inhibitor-treated cells continually became extended/respread up to 3 h with an associated increase in actin stress fibers that was preceded by an acute 1.6-fold Cai2+ increase. In contrast, control or PKC activator-treated cells (phorbol 12,13-dibutyrate or 12-O-tetradecanoylphorbol-13-acetate; TPA) contracted/retracted within 5 min in response to PTH. A role for Cai2+ in PTH-induced cell spreading was further indicated by a contractile response to PTH when PKC-inhibitor-treated cells were loaded with the intracellular calcium chelator dimethyl BAPTA (3 microM x 30 min). PTH-induced Cai2+ increases in adherent PKC inhibitor-treated cells were also associated with a 1.8-fold 1,4,5-IP3 increase as measured by mass assay. The data suggest PKC contributes to UMR 106-H5 cell morphology and selectively regulates signal pathways activated by PTH to promote either cell contraction (cAMP) or extension (1,4,5-IP3/Cai2+).
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PMID:Protein kinase C modulator effects on parathyroid hormone-induced intracellular calcium and morphologic changes in UMR 106-H5 osteoblastic cells. 913 85

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.
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PMID:Anthrax toxin: pathologic effects on the cardiovascular system. 1927 4

Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.
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PMID:Anthrax Pathogenesis. 2619 5