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)

Aggregating cells of Dictyostelium discoideum are able to release cyclic AMP periodically. The oscillations of cAMP generation are associated with changes in adenylate cyclase activity. Cyclic AMP receptors on the cell surface are functionally coupled to the oscillating system as evidenced by phase shifts that are induced by small pulses of extracellular cAMP. An important element of the oscillating system is the signal processing from surface receptors to the adenylate cyclase. This pathway exhibits adaptation resulting in the suppression of responses to constant, elevated concentrations of cAMP. The signal input for adenylate cyclase activation is, therefore, a change in the extracellular cAMP concentration with time. Oscillations in the absence of detectable changes of intra- or extracellular cAMP concentrations suggest the possibility that there is a metabolic network in D. discoideum cells that undergoes oscillations without coupling to adenylate cyclase. Cyclic GMP concentrations oscillate with a slight phase difference in advance of that of cAMP, suggesting that the two nucleotide cyclases might not be activated by the same mechanism. Elevation of extracellular calcium exerts an inhibitory effect on the accumulation of cAMP and on the second of the two cGMP peaks.
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PMID:Oscillations of cyclic nucleotide concentrations in relation to the excitability of Dictyostelium cells. 4 79

Following the initiation of development, amoebae of Dictyostelium discoideum aggregate chemotactically toward cyclic AMP (cAMP). Adenyl cyclase, cAMP phosphodiesterase, and cAMP binding sites all increase 20--40 fold during the first few hours of development. It has been shown that addition of 1 mM EDTA and 5 mM MgCl2 accelerates the aggregation process. Likewise, the calcium ionophore, A23187, leads to precocious aggregation while 4 X 10(-5) M progesterone considerably delays it. These treatments have now been shown to result in increased accumulation of adenyl cyclase in the case of EDTA and Mg2+ or the ionophore and greatly decreased accumulation in the case of the steroid. Treatment with EDTA and Mg2+ or the ionophore has been shown not only to accelerate aggregation in wild-type amoebae but to overcome complete blocks to aggregation in certain mutant strains. We have found that addition of Mn2+ will also permit aggregation of mutant cells otherwise unable to aggregate. This divalent ion, unlike EDTA and Mg2+ or the ionophore, was shown to directly stimulate adenyl cyclase. Calcium ions were also found to affect the enzyme such that at Ca2+ concentrations found within the cells the great majority of the activity is inhibited. Manganese ions can overcome the inhibition by Ca2+. These findings show that conditions which stimulate aggregation result in increased activity of adenyl cyclase either by increased accumulation of the enzyme or by increased activity of the available enzyme, and support the proposed central role of adenyl cyclase in aggregation.
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PMID:The effect of divalent cations on aggregation of Dictyostelium discoideum. 10 68

A modified version of an allosteric model for adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] previously analyzed for sustained oscillations of adenosine 3':5'-cyclic monophosphate (cAMP) in Dictyostelium discoideum [Goldbeter, A. (1975) Nature 253, 540-542] is examined to see whether it can account for the relay of cAMP pulses. Oscillations occur around a nonequilibrium, unstable stationary state when system parameters are in a certain domain. It is found that relay can occur outside this domain, in a restricted set of parameter values for which the solution ultimately tends to a stable steady state. A suprathreshold level of extracellular cAMP is needed to elicit relay which consists in a pulsatory synthesis of intracellular cAMP. Theoretical predictions are compared with the results of experiments on cAMP relay and oscillation in aggregation-competent cells of D. discoideum. The model suggests an explanation for the emergence of aggregation centers and for a sequence of developmental events observed in interphase amoebae.
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PMID:Unified mechanism for relay and oscillation of cyclic AMP in Dictyostelium discoideum. 19 5

The cAMP receptor on the surface of aggregation competent Dictyostelium discoideum cells specifically binds [3H]cAMP in an oscillatory manner with a periodicity of 2 min. The oscillatory cAMP-binding component is developmentallly regulated and has the nucleotide specificity expected for recognition of chemotactic signals. The concentration dependence of the peak amplitudes of cAMP binding exhibit an apparent threshold at 10(-8) M cAMP. The threshold concentration for cAMP binding that we measure is consistent with the concentration dependence of signal relay (cAMP secretion) and the chemotactic response. The kinetic data of binding and dissociation are very rapid, consistent with the time course of oscillations in receptor capacity (affinity). Specific binding oscillations are destroyed by heat or chymotrypsin but are insensitive to trypsin or glycosidase. A plasma membrane localization of receptor is supported by enrichment of cAMP binding in a plasma membrane preparation from differentiated cells. Receptor oscillations with a 2-min period are preserved in the membrane preparations, and the peak amplitudes are increased about 10-fold consistent with the enrichment of other plasma membrane markers. The alternating change in the receptor's binding capacity for cAMP may be the basis of the relay refractory period as well as the primary oscillator involved in the generation of postreceptor events such as stimulation of adenylate cyclase, cAMP secretion, and cellular movement, all of which have been previously shown to oscillate.
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PMID:Properties of the oscillatory cAMP binding component of Dictyostelium discoideum cells and isolated plasma membranes. 22 58

Adenylate cyclase activity and endogenous cyclic AMP levels were measured using a highly sensitive radioimmunoassay and protein binding assay during 24 h of development of Dictyostelium discoideum. Adenylate cyclase activity was not detected until the aggregation stage of development (10 h) when a sudden peak of activity was found. The enzyme was active at all subsequent stages, although a slow decline in activity was observed. Similarly, cyclic AMP levels were not detectable through the first 7 h of development and then showed a sudden peak at aggregation. Following aggregation the cyclic AMP levels decreased to approximately 1/2 the peak value and maintained that level throughout the remainder of the developmental cycle. Adenylate cyclase had a narrow range of substrate saturation with a maximum velocity at 1 to 4 mM ATP at both the aggregation stage (10 h) and the sorocarp stage (24 h). At levels of ATP higher than 6 mM the enzyme from both stages was strongly inhibited. No activity was observed in the absence of Mg2+ or dithiothreitol. The activity from 10-, 14-, and 20-h stages was found bound to a 25,000 x g pellet fraction. The sudden appearance of adenylate cyclase and its product cyclic AMP at aggregation provides additional evidence of a role for this nucleotide in chemotaxis, and the retention of enzyme activity and nucleotide level during the subsequent stages may reflect a further function of cyclic AMP during formation of the two cell types.
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PMID:Adenylate cyclase activity and cyclic AMP levels during the development of Dictyostelium discoideum. 22 25

In this study we report that preincubation of Dictyostelium discoideum membrane-bound adenylate cyclase with ATP over the concentration range 0.5 to 100 mM results in a loss of catalytic activity and that this effect persists even after removal of ATP. An analysis of the time course of this effect shows that, at 25 mM ATP, a 5- to 10-min preincubation results in 50% loss of activity. Additional studies on this effect showed that anhydride bond cleavage of ATP occurs during the preincubation. However, loss of catalytic activity is not porduced by ADP, AMP, cAMP, adenosine, pyrophosphate, or phosphate either separately or in pairs. Further, using the structural analogs adenosine 5'-(alpha, beta-methylene)triphosphate and adenyl-5'-yl imidodiphosphonate, we show that there is a direct correlation between alpha-beta-phosphoanhydride bond cleavage and the loss of catalytic activity. These results can be interpreted in terms of two classes of reaction mechanisms: either those involving covalent modifications or those involving a ligand-induced slow conversion of the adenylate cyclase from an active to an inactive form. Additional studies show that the addition of AMP to the reaction mixture, as well as removal of the membrane-bound 5'-nucleotidase activity, can prevent the loss of cyclase activity. These results suggest not only that adenylate cyclase activity is related to the AMP:ATP ratio but that the cyclase activity can be modified by the level of 5'-nucleotidase activity. Studies on the duration of the loss of activity produced by ATP show that following removal of ATP and additional incubation, a gradual recovery of cyclase activity is observed. This result suggests that under appropriate conditions the cyclase inactivation by ATP is reversible.
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PMID:Time-dependent changes in Dictyostelium discoideum adenylate cyclase activity upon incubation with ATP. 98 25

In Dictyostelium discoideum cells the enzyme adenylate cyclase is functionally coupled to cell surface receptors for cAMP. Coupling is known to involve one or more G-proteins. Receptor-mediated activation of adenylate cyclase is subject to adaptation. In this study we employ an electropermeabilized cell system to investigate regulation of D. discoideum adenylate cyclase. Conditions for selective permeabilization of the plasma membrane have been described by C.D. Schoen, J. C. Arents, T. Bruin, and R. Van Driel (1989, Exp. Cell Res. 181, 51-62). Only small pores are created in the membrane, allowing exchange of exclusively low molecular weight substances like nucleotides, and preventing the loss of macromolecules. Under these conditions functional protein-protein interactions are likely to remain intact. Adenylate cyclase in permeabilized cells was activated by the cAMP receptor agonist 2'-deoxy cAMP and by the nonhydrolyzable GTP-analogue GTP gamma S, which activates G-proteins. The time course of the adenylate cyclase reaction in permeabilized cells was similar to that of intact cells. Maximal adenylate cyclase activity was observed if cAMP receptor agonist or GTP-analogue was added just before cell permeabilization. If these activators were added after permeabilization adenylate cyclase was stimulated in a suboptimal way. The sensitivity of adenylate cyclase activity for receptor occupation was found to decay more rapidly than that for G-protein activation. Importantly, the adenylate cyclase reaction in permeabilized cells was subject to an adaptation-like process that was characterized by a time course similar to adaptation in vivo. In vitro adaptation was not affected by cAMP receptor agonists or by G-protein activation. Evidently electropermeabilized cells constitute an excellent system for investigating the positive and negative regulation of D. discoideum adenylate cyclase.
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PMID:Regulation of adenylate cyclase in electropermeabilized Dictyostelium discoideum cells. 131 Apr 72

A human ovarian small cell carcinoma line (BIN-67) expresses abundant calcitonin (CT) receptors (CTR) (143,000 per cell) that are coupled, to adenylate cyclase. The dissociation constants (Kd) for the CTRs on these BIN-67 cells is approximately 0.42 nM for salmon CT and approximately 4.6 nM for human CT. To clone a human CTR (hCTR), a BIN-67 cDNA library was screened using a cDNA probe from a porcine renal CTR (pCTR) that we recently cloned. One positive clone of 3,588 bp was identified. Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = approximately 0.44 nM) and for human CT (Kd = approximately 5.4 nM). The expressed hCTR was coupled to adenylate cyclase. Northern analysis with the hCTR cDNA probe indicated a single transcript of approximately 4.2 kb. The cloned cDNA encodes a putative peptide of 490 amino acids with seven potential transmembrane domains. The amino acid sequence of the hCTR is 73% identical to the pCTR, although the hCTR contains an insert of 16 amino acids between transmembrane domain I and II. The structural differences may account for observed differences in binding affinity between the porcine renal and human ovarian CTRs. The CTRs are closely related to the receptors for parathyroid hormone-parathyroid hormone-related peptide and secretin; these receptors comprise a distinct family of G protein-coupled seven transmembrane domain receptors. Interestingly, the hCTR sequence is remotely related to the cAMP receptor of Dictyostelium discoideum (21% identical), but is not significantly related to other G protein-coupled receptor sequences now in the data bases.
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PMID:Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line. 133 Nov 73

Binding of an intrinsic agonist (cAMP) to specific receptors on the cell surface induces transmembrane signals for activation and desensitization (adaptation and down regulation) of adenylate cyclase in the cellular slime mold, Dictyostelium discoideum. It is generally believed that dithiothreitol (DTT) induces the activation through interaction between the receptor and gradually accumulated cAMP, since DTT is known to inhibit cAMP-phosphodiesterase which degrades cAMP. In the present paper, we investigated the mechanism of activation of adenylate cyclase by the thiol-reducing agents, DTT and 2,3-dimercapto-1-propanol (BAL). We found that BAL activated adenylate cyclase transiently even under conditions where the intrinsic agonist supersaturated the cAMP-receptors and competitively inhibited phosphodiesterase. This result is inconsistent with the generally accepted notion. We conclude that BAL has an independent effect from those of the intrinsic agonist (cAMP) and phosphodiesterase in activation of adenylate cyclase. Since BAL could induce activation just after the activation induced by a supersaturating concentration of the intrinsic agonist had ceased, the independent effect of BAL is not a simple enhancement of the cAMP-induced activation. Our result also suggests that the cAMP-induced adaptation (but not down regulation) suppresses the BAL-induced activation while BAL itself does not induce adaptation to cAMP or BAL. We propose that the thiol-reducing reagent induces or modifies the transmembrane activation signal for adenylate cyclase.
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PMID:Reducing reagent-induced activation of adenylate cyclase in the cellular slime mold, Dictyostelium discoideum. 166 89

Dictyostelium cells use extracellular cyclic AMP both as a chemoattractant and as a morphogen inducing cell-type-specific gene expression. Cyclic AMP binds to surface receptors, activates one or more G-proteins, and stimulates adenylate cyclase, guanylate cyclase and phosphoinositidase C. Mutant fgdC showed aberrant chemotaxis, and was devoid of cyclic AMP-induced gene expression and differentiation. Both the receptor- and G-protein-mediated stimulation of adenylate cyclase and guanylate cyclase were unaltered in mutant fgdC as compared to wild-type cells. In wild-type cells phosphoinositidase C was activated about twofold by the cyclic AMP receptor. In mutant fgdC cells, however, the enzyme was inhibited by about 60%. These results suggest that phosphoinositidase C is regulated by a receptor-operated activation/inhibition switch that is defective in mutant fgdC. We conclude that activation of phosphoinositidase C is essential for Dictyostelium development.
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PMID:Abberant chemotaxis and differentiation in Dictyostelium mutant fgdC with a defective regulation of receptor-stimulated phosphoinositidase C. 166 62


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