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)

Concanavalin A (Con A) is a tetrameric plant lectin that disrupts plasma membrane-cytoskeletal interactions and alters plasma membrane fluidity. We used Con A as a probe to explore beta-adrenergic and muscarinic cholinergic receptor-mediated regulation of cAMP in intact neonatal rat ventricular myocytes. Preincubation with Con A, 0.5 micrograms/ml, attenuated 1 microM (-)-norepinephrine (NE)-induced downregulation of beta-adrenergic receptors and resulted in a 50% augmentation of cAMP accumulation stimulated by 1 microM NE. Con A also augmented forskolin (1-10 microM)-stimulated cAMP accumulation by an average of 37% (P less than 0.05); however, Con A preincubation had no effect on basal or cholera toxin-stimulated cAMP content. The muscarinic cholinergic agonist carbachol (1-100 microM) decreased 1 microM NE-stimulated cAMP generation by an average of 32% (n = 7, P less than 0.05); preincubation with Con A further enhanced the inhibitory effect of carbachol by 18% (n = 7, P less than 0.05). Carbachol (1 microM) for 2 h decreased muscarinic cholinergic receptor density in whole cells by 33%; preincubation with Con A prevented this receptor downregulation. Con A pretreatment did not affect (-)-isoproterenol- or forskolin-stimulated adenylate cyclase activity in cell homogenates, suggesting that an intact cytoarchitecture is necessary for Con A to augment cAMP formation. We conclude that Con A, through its modulation of beta-adrenergic and muscarinic cholinergic receptor signaling, amplifies both stimulatory and inhibitory adenylate cyclase-linked pathways in intact neonatal ventricular myocytes. These data suggest the possibility that plasma membrane-cytoskeletal interaction is an important regulator of transmembrane signaling because interference with this interaction results in alterations in cAMP accumulation mediated by both beta-adrenergic- and muscarinic cholinergic-adenylate cyclase pathways.
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PMID:Concanavalin A amplifies both beta-adrenergic and muscarinic cholinergic receptor-adenylate cyclase-linked pathways in cardiac myocytes. 165 74

The orientation of the enzyme Mg(2+)-ATPase (EC 3.6.1.3) in the transverse tubule (TT) membranes of skeletal muscle was investigated using highly purified chicken and rabbit TT vesicles. The percentage of sealed vesicles present in these preparations averaged 88 and 78%, respectively, as calculated from the detergent-induced increase in ouabain-sensitive (Na+, K+)-ATPase activity, ATP-dependent ouabain binding, and lactate dehydrogenase activity (sarcoplasmic enzyme trapped in the TT vesicles). Sidedness of the sealed vesicles, estimated from latency of 5'-nucleotidase, acetylcholinesterase, and adenylate cyclase, was predominantly right-side out (69-76%, chicken TT and 62-70%, rabbit TT). In both chicken and rabbit native vesicles, high Mg(2+)-ATPase activity was detected by addition of ATP to the extravesicular medium; this activity was increased 14-12% by alamethicin pointing to the external localization of the active site. Furthermore, the enzymatic activity resulted partially inhibited by treatment of the chicken TT vesicles with proteinase K or p-hydroxymercuribenzoate. Concanavalin A stimulated 4-fold the chicken TT Mg(2+)-ATPase activity, an effect not potentiated by detergent permeabilization of the intact vesicles, indicating that lectin-binding sites were also solvent accessible. This stimulatory effect was not observed in native or permeabilized rabbit TT vesicles. From these results we conclude that the TT Mg(2+)-ATPase is an ectoenzyme with its nucleotide-hydrolyzing site and glycosylated regions facing the extracellular space. Inhibitors of ion-motive ATPases did not modify the enzyme activity, suggesting a different physiological role for the TT Mg(2+)-ATPase which may be involved in the regulation of muscle fiber functions affected by extracellular ATP levels.
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PMID:Transverse tubule Mg(2+)-ATPase of skeletal muscle. Evidence for extracellular orientation of the chicken and rabbit enzymes. 166 Apr 76

Human peripheral blood mononuclear cells (H-PBMC) from 10 healthy donors were stimulated to proliferate with phytohemagglutinin lectin (PHA), anti-CD3 monoclonal antibody (mAb), and anti-CD3 mAb plus phorbol 12, myristate 13 acetate (TPA), a protein kinase C (PKC) agonist. Anti-CD3 mAb-mediated mitogenesis was 35-75% of that observed with PHA. When TPA was added to a dose of mAb that by itself did not cause mitogenesis, proliferation equal to 50-90% of the maximally mitogenic dose occurred. TPA did not enhance proliferation with maximally mitogenic doses of antibody. Dimethyl-prostaglandin E2, dibutyryl cyclic AMP, and forskolin (an adenyl cyclase agonist) inhibited PHA, anti-CD3, and anti-CD3/PMA-mediated mitogenesis. Cyclosporine (CSA) inhibited anti-CD3 and anti-CD3/TPA mitogenesis in a dose-dependent fashion. While CSA inhibited anti-CD3 and anti-CD3/TPA mitogenic signals, it did not affect PGE2 production by anti-CD3 mAb-stimulated H-PBMC. In the presence of CSA, PGE2 production in PHA-stimulated H-PBMC was increased. PGE2 inhibits lymphocyte proliferation via a cyclic AMP-mediated mechanism and may enhance maturation of suppressor cells. CSA inhibits anti-CD3 mAb and anti-CD3/TPA proliferative signals in H-PBMC yet has no effect or may even enhance production of suppressive PGE2. The maturation of antigen-specific suppressor cells elicited by CSA may involve active down-regulation of CD3 receptor and PKC-dependent events while PGE2 production continues.
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PMID:Cyclosporine effect on anti-CD3 monoclonal antibody-stimulated mitogenesis, phorbol ester comitogenesis, and PGE2 production. 182 79

In this paper we examine the characteristics of human cytolytic T lymphocytes (CTL) generated in the presence of forskolin and PGE2. Forskolin and PGE2 suppressed the generation of class-I-specific CTL. The CTL generated in the presence of forskolin and PGE2 had different characteristics which included their ability to proliferate in response to the alloantigen and their lectin-mediated cytolytic activity. The CTL generated in the presence of forskolin had normal proliferative response to the alloantigen, whereas the CTL generated in the presence of PGE2 showed a suppressed proliferative ability to the alloantigen. The two groups of CTL were then tested for their activity in the process of lectin-dependent cell-mediated cytotoxicity. After the addition of PHA into the chromium release assay the CTL generated in the presence of forskolin normally lysed the nonspecific targets, whereas the CTL generated in the presence of PGE2 did not show the normal response in lysing the nonspecific targets. The results suggest that the cytolytic machinery was intact when the CTL were generated in the presence of forskolin but CTL were not able to either recognize or lyse the target cell. However, the CTL generated in the presence of PGE2 did not share the same characteristics as the CTL generated in the presence of forskolin because the CTL generated in the presence of PGE2 were unable to kill even in the presence of lectin. It appears that the inhibitory effects of forskolin were mediated by cAMP and not by its effects on the potassium channels because the 1,9-dideoxy derivative of forskolin which did not activate adenylate cyclase also did not suppress the generation of CTL. However, it was not established whether the diverse effects of PGE2 on the generation of CTL were mediated by cAMP-dependent, -independent or by both mechanisms.
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PMID:Forskolin and prostaglandin E2 regulate the generation of human cytolytic T lymphocytes. 197 71

Agglutination of human platelets by bovine von Willebrand factor (vWF) or by human vWF in the presence of ristocetin is inhibited by ADP and by several other platelet agonists but not by epinephrine. Vincristine, which causes a shape change by disrupting microtubules, neither inhibited agglutination nor blocked the effect of ADP. The action of ADP was blocked by ATP, by p-fluorosulfonylbenzoyladenosine, and by the thiol-reactive regents cytochalasin A and p-chloromercuribenzenesulfonate. In contrast to its effects on vWF, ADP enhanced agglutination induced by wheat germ lectin. ADP caused a small decrease in the number and affinity of binding sites for vWF on platelets, too small to explain the inhibition of agglutination. The ability of ADP and other agonists to inhibit agglutination appears to be related neither to inhibition of adenylate cyclase nor to the loss of their discoid shape but rather to the membrane changes that accompany the shape change.
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PMID:Effect of platelet activation on the agglutination of platelets by von Willebrand factor. 215 74

The subcellular distribution of the alpha 2-adrenergic receptor, pertussis-toxin substrates (Gi, the inhibitory G-protein) and adenylate cyclase was determined in human platelets. The alpha 2-adrenergic receptor and pertussis-toxin substrate activity codistribute with surface membranes identified by a novel fluorescent-lectin method. The platelet granule fractions did not contain detectable Gi. Only 2-4% of the total pertussis-toxin substrate activity appears in soluble fractions, and this amount was not increased upon addition of purified beta gamma units or after pretreatment of platelets with adrenaline. There is no evidence for compartmentation of the alpha 2-adrenergic receptor or Gi to account for the low-affinity component of agonist binding to the alpha 2-adrenergic receptor in human platelet membranes. Translocation of Gi from plasma membrane to platelet cytosol or granules does not appear to play any significant role in the mechanism of alpha 2-receptor-mediated platelet activation.
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PMID:Subcellular distribution of alpha 2-adrenergic receptors, pertussis-toxin substrate and adenylate cyclase in human platelets. 215 68

Extracellular calcium (Ca2+) is the major physiological regulator of parathyroid function; high Ca2+ decreases PTH secretion as well as reduces cAMP accumulation. There is an increasing body of evidence suggesting the presence of a receptor-like mechanism at the surface of the parathyroid cell which mediates these and other actions of Ca2+. In the present studies we used the lectin Concanavalin-A (Con-A) to investigate the possible role of carbohydrate moieties in the regulation of cAMP metabolism by Ca2+ in bovine parathyroid cells, which is thought to involve inhibition of adenylate cyclase via activation of the guanine nucleotide regulatory protein Gi. Pretreatment of parathyroid cells with Con-A for 15-60 min significantly reversed the inhibitory effect of high Ca2+ on dopamine-stimulated cAMP accumulation, reducing the inhibition at 3 mM Ca2+ from 70 +/- 3% to 30 +/- 3%. This effect was also observed in the absence of preincubation and with concentrations of Con-A as low as 40 micrograms/ml and was reversed by alpha-methyl-D-glucoside, a specific antagonist of the lectin. The lectin also reversed the inhibitory effects of Ca2+ (2-3 mM) on cAMP accumulation stimulated by isoproterenol and forskolin to a comparable extent. Prostaglandin F2 alpha-induced inhibition of cAMP accumulation (likewise mediated by Gi) was, however, not reversed by Con-A, suggesting that the lectin did not have a generalized effect on the cell surface or on receptors inhibiting adenylate cyclase. Moreover, fluoride-induced inhibition of cAMP accumulation was not reversed by Con-A, providing additional evidence that the lectin did not act at or distal to Gi (i.e. modulate Gi, adenylate cyclase, and/or phosphodiesterase). The present study suggests that Con-A may modulate the actions of extracellular Ca2+ on parathyroid secretion, possibly modifying the interaction of Ca2+ with the cell surface by affecting carbohydrate moieties that seem to be important in the Ca2(+)-sensing process. The structural element involved in Ca2+ sensing in the parathyroid cell may be a glycoprotein or closely associated with glycoproteins with carbohydrate chains containing alpha-methyl-D-glycoside.
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PMID:Effect of the lectin concanavalin-A on calcium-regulated adenosine 3',5'-monophosphate accumulation in bovine parathyroid cells. 215 77

The rate of growth and orientation of embryonic Xenopus nerves exposed to pharmacological agents, to an applied electric field or to both simultaneously were studied. The adenyl cyclase activator forskolin (100 microM) induced a threefold increase in the rate of elongation, as did an electric field alone. Together, their effect in augmenting rate of growth was additive, but only at a concentration of 50 microM forskolin. The normal pattern of faster growth towards cathode than anode was not present in nerves treated with the lectin concanavalin A, which also inhibits normal turning behaviour towards the cathode. Nerve orientation towards the cathode and augmented rates of growth were found in the presence of forskolin or ganglioside GM1. It is suggested that a combined approach of drug treatment and an applied electric field may be useful in promoting nerve regeneration.
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PMID:Nerve growth in a small applied electric field and the effects of pharmacological agents on rate and orientation. 238 31

Previous studies have shown that maturational changes can be induced in a human monocyte line, U937, by treatment with cellfree medium from lectin-stimulated cloned human T lymphocytes or the vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3). Many of the maturational effects are accompanied by modification, new synthesis, or reorganization of cell surface membrane constituents, including proteins that function as receptors for ligands that modulate monocyte function. In the present studies, we examined the effects of monocyte differentiation on responsiveness to prostaglandin E2 (PGE)2. We found that the maturational effects of the lymphokine or 1,25[OH]2D3 were accompanied by a marked reduction in the PGE2-induced increase in cellular content of adenosine 3':5'-cyclic monophosphate (cAMP) and a shift in the dose-response curve consistent with a decrease in PGE2 receptor number or binding affinity. Incubation of cells with IFN-alpha or IFN-gamma produced by recombinant DNA technology did not influence PGE2 responsiveness, suggesting that the effects of the lymphokine were not mediated by these products. The absence of an effect on sodium fluoride- or forskolin-induced adenylate cyclase response in membranes prepared from treated cells suggests that the treatment conditions affect PGE2 receptor function rather than the adenylate cyclase enzyme complex. Changes in cell surface receptors for hormones such as PGE2 provide a potential mechanism for modulating the biologic activity of monocyte-macrophages during the process of cellular differentiation.
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PMID:The adenosine 3':5'-cyclic monophosphate response to prostaglandin E2 is altered in U937 cells in association with maturational events induced by activated T lymphocytes and 1,25-dihydroxyvitamin D3. 242 Aug 90

Aprotinin caused a dose-dependent inhibition of [125I]hCG binding to its receptor in plasma membranes prepared from luteinized rat ovaries. Displacement of [125I]hCG from its receptor by aprotinin was temperature dependent, with an ID50 of 300 microM at 4 C and an ID50 of 3700 microM at 22 C. Equilibrium binding data showed a decrease in the Ka for hCG in the presence of increasing concentrations of aprotinin; aprotinin had no effect on the number of binding sites. The rate of association of hCG with its receptor was markedly reduced in the presence of aprotinin, but aprotinin had little effect on the rate of dissociation. Control experiments established that aprotinin did not inhibit the binding of [125I]hCG to its receptor due to its lectin properties, an ionic effect or some irreversible impairment of the receptor or hormone. Aprotinin did not inhibit hCG binding when the receptor was solubilized out of ovarian membranes with Triton X-100. Aprotinin inhibited the hCG-mediated activation of adenylate cyclase in rat ovarian plasma membranes in a dose-dependent manner. Similarly, aprotinin antagonized the hCG-stimulated biosynthesis of progesterone by dispersed rat luteal cells. The maximal agonistic activity of hCG was attenuated in these two bioassays. The data are compatible with a hypothesis that aprotinin sterically hinders the entry of hCG into its receptor site by binding to a protease in the plasma membrane that is closely associated with the hCG receptor. This proposal is consistent with the emerging concept that integral membrane proteases are modulators of receptor function.
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PMID:Aprotinin antagonizes the binding of human chorionic gonadotropin to its receptor. 243 30


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