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)

The attachment of a diphtheria toxin-specific synthetic antigenic determinant and a synthetic adjuvant to a synthetic polymeric carrier led to production of a totally synthetic macromolecule which provoked protective antibodies against diphtheria when administered in aqueous solution. When peptides related to the B subunit of cholera toxin were synthesized and attached to tetanus toxoid, antibodies produced against the conjugate reacted in some but not all cases with intact cholera toxin and (especially with peptide CTP 3, residues 50-64) neutralized toxin reactivity, as tested by permeability in rabbit skin, fluid accumulation in ligated small intestinal loops and adenylate cyclase activation. Polymerization of the peptide without any external carrier, or conjugation with the dipalmityl lysine group, had as good an effect in enhancing the immune response as its attachment to tetanus toxoid. Prior exposure to the carrier suppressed the immune response to the epitope attached to it, whereas prior exposure to the synthetic peptide had a good priming effect when the intact toxin was given; when two different peptides were attached to the same carrier, both were expressed. Antisera against peptide CTP 3 were highly cross-reactive with the heat-labile toxin of Escherichia coli and neutralized it to the same extent as cholera toxin, which is not surprising in view of the great homology between the two proteins. A synthetic oligonucleotide coding for CTP 3 has been used to express the peptide in a form suitable for immunization. It led to a priming effect against the intact cholera toxin.
 ...
PMID:Synthetic peptides with antigenic specificity for bacterial toxins. 242 52

Forskolin, a potent activator of adenylate cyclase, was examined for its ability to alter human peripheral blood lymphocyte (HPBL) activation by both mitogens and antigens. We found that forskolin, at concentrations ranging from 0.04 to 25 micrograms/ml, caused a dose-dependent inhibition of HPBL responses to mitogens (concanavalin A, phytohemagglutinin, pokeweed mitogen and Staphylococcus aureus) and to recall antigens (tetanus toxoid and streptokinase/streptodornase). Inhibition was reflected in altered DNA, RNA and protein synthesis, including immunoglobulin production, and was not due to altered cell viability. Forskolin also induced a 19-fold increase in HPBL cyclic AMP levels at the same concentrations that suppressed HPBL function. To further define the mechanism(s) by which these elevations in cyclic AMP suppressed HPBL function, we tried to reverse these inhibitory effects with several agents; ascorbic acid, carbachol and levamisole had no effect. However, the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate, as well as L-alpha-1,2-dioleoyl diacylglycerol were able to completely reverse the inhibition. Furthermore, the Ca2+ ionophore, ionomycin, was also able to act synergistically with lower and less effective concentrations of 12-O-tetradecanoyl phorbol 13-acetate to reverse the inhibitory effects of forskolin. The data suggest that forskolin-induced elevations in cyclic AMP may lead to inhibition (or, more correctly, prevents the activation) of protein kinase C, presumably by inhibiting phospholipid turnover. Our studies suggest a linkage between these two opposing membrane-signal transduction systems with protein kinase C representing a pivotal point for various regulatory signals that ultimately control lymphocyte activation and function.
 ...
PMID:Suppression of human lymphocyte responsiveness by forskolin: reversal by 12-O-tetradecanoyl phorbol 13-acetate, diacylglycerol and ionomycin. 303 53

Many bacterial toxins are proteins, encoded by the bacterial chromosomal genes, plasmids or phages. Lysogenic phages form part of the chromosome. The toxins are usually liberated from the organism by lysis, but some are shed with outer membrane proteins in outer membrane vesicles. An important non-protein toxin is lipopolysaccharide or endotoxin, which is a constituent of the cell wall of gram negative bacteria. Toxins may damage the eukaryotic cell membrane by combining with some structural component, or otherwise alter its function. Many toxins combine with specific receptors on the surface membrane, frequently glycoproteins or gangliosides, and penetrate the cell to reach their intracellular target. A common mechanism of entry is absorptive endocytosis. Many protein toxins have an A-B structure, B being a polypeptide which binds to the receptor and A being an enzyme. Many toxins are activated, either when produced by the bacterium or when bound to the membrane receptor, by proteases (nicking). An enzymatic process common to many toxins is adenosine diphosphate (ADP)-ribosylation of the adenylate cyclase regulatory proteins, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). This is the mechanism of action of cholera toxin. Diphtheria toxin catalyzes the transfer of ADP-ribose to elongation factor-2, inhibiting protein synthesis. Most toxins act on the target cells to which they bind, but tetanus toxin, and, to a lesser degree, botulinum toxin, ascend axons and affect more distant structures. Although many toxin effects caused by bacteria have been described, only a few toxins have been identified, characterized, and their mode of action determined at the molecular level. The best known of these are discussed.
 ...
PMID:Bacterial toxins. 328 62

Blockade of electrical activity in dissociated spinal cord cultures results in a significant loss of neurons during a critical period in development. Decreases in neuronal cell numbers and 125I-labeled tetanus toxin fixation produced by electrical blockade with tetrodotoxin (TTX) were prevented by addition of vasoactive intestinal peptide (VIP) to the nutrient medium. The most effective concentration of VIP was 0.1 nM. At higher concentrations, the survival-enhancing effect of VIP on TTX-treated cultures was attenuated. Addition of the peptide alone had no significant effect on neuronal cell counts or tetanus toxin fixation. With the same experimental conditions, two closely related peptides, PHI-27 (peptide, histidylisoleucine amide) and secretin, were found not to increase the number of neurons in TTX-treated cultures. Interference with VIP action by VIP antiserum resulted in neuronal losses that were not significantly different from those observed after TTX treatment. VIP10-28, a fragment that inhibits VIP stimulation of adenylate cyclase, also produced a dose-dependent decrease in neuronal cell counts similar to that seen with TTX treatment. These data indicate that under conditions of electrical blockade a neurotrophic action of VIP on neuronal survival can be demonstrated.
 ...
PMID:Vasoactive intestinal peptide and electrical activity influence neuronal survival. 345 68

The thyrotropin (TSH) receptor has been proposed to be composed of a membrane glycoprotein and a membrane ganglioside, the former important in high affinity recognition, the latter vital for message coupling to the adenylate cyclase system. The present study used two approaches, formation of antireceptor monoclonal antibodies and reconstitution, to validate the model and further examine the role of the ganglioside. Three kinds of monoclonal antireceptor antibodies are defined. One group which inhibits TSH binding and TSH functions, i.e., TSH-stimulated adenylate cyclase activity, iodide uptake, and thyroid hormone release, is shown to be directed against the glycoprotein component of the receptor. The second group includes antibodies which mimic TSH in all stimulatory actions, are competitive agonists of TSH, are equivalent to thyroid stimulating antibodies in the sera of patients with Graves' disease, and are directed against the ganglioside component of the receptor. These stimulating monoclonal antibodies are directed against a minor ganglioside membrane component which fractionates as a disialoganglioside. When this ganglioside is incorporated into 1-8 thyroid cells which have a correlated ganglioside deficiency and TSH receptor defect, reconstitution of TSH stimulated adenylate cyclase activity occurs. Whereas the first group of antibodies inhibits TSH-stimulated function, they do not inhibit the stimulatory antibodies which mimic TSH, an observation consistent with the 2 component hypothesis of the receptor model. The third group of antibodies have a mix of properties from the first two groups and suggests that the TSH receptor in situ is an actual complex of the two components or that there are common carbohydrate determinants in the functional sites of each receptor component. Implications of a TSH receptor structure in which its ganglioside and glycoprotein components are in equilibrium with pools of free components and, in turn, components important for cholera toxin, tetanus toxin and interferon receptors are discussed. In regard to the pathogenesis of Graves' disease, the data indicate that thyroid stimulating autoantibodies are autoimmune equivalents of cholera toxin with respect to the importance of ganglioside function. Since antiidiotype studies of antibodies against TSH confirm a structural relationship between receptors for thyrotropin, cholera toxin, and thyroid stimulating autoantibodies, the data establish an unequivocal role for the ganglioside in TSH receptor structure which facilitates interpretation of in vitro experiments aimed at understanding the mechanism of ganglioside-ligand interactions.
 ...
PMID:Gangliosides, the thyrotropin receptor, and autoimmune thyroid disease. 633 Nov 33

The immune response against six synthetic peptides corresponding to various segments of the B subunit of cholera toxin was evaluated. Conjugates in which the peptides were covalently linked to tetanus toxoid served for immunization of rabbits. As previously reported, four of these conjugates elicited antibodies cross-reactive with intact cholera toxin. We report here that antisera against two of these synthetic peptides inhibit the entire spectrum of activities of the intact cholera toxin. This is manifested both on the biochemical level (adenylate cyclase induction) and on the biological effect (intestinal fluid secretion). These results indicate that these peptides may serve as suitable candidates for preparation of a synthetic anticholera vaccine.
 ...
PMID:Both cholera toxin-induced adenylate cyclase activation and cholera toxin biological activity are inhibited by antibodies against related synthetic peptides. 659 65

Gangliosides are complex glycosphingolipids that contain from one to several residues of sialic acid. They are present in the plasma membrane of vertebrate cells with their oligosaccharide chains exposed to the external environment. They have been implicated as cell surface receptors and several bacterial toxins have been shown to interact with them. Cholera toxin, which mediates its effects on cells by activating adenylate cyclase, bind with high affinity and specificity to ganglioside GM1. Toxin-resistant cells which lack GM1 can be sensitized to cholera toxin by treating them with GM1. Cholera toxin specifically protects GM1 from cell surface labeling procedures and only GM1 is recovered when toxin-receptor complexes are isolated by immunoadsorption. These results clearly demonstrate that GM1 is the specific and only receptor for cholera toxin. Although cholera toxin binds to GM1 on the external side of the plasma membrane, it activates adenylate cyclase on the cytoplasmic side of the membrane by ADP-ribosylation of the regulatory component of the cyclase. GM1 in addition to functioning as a binding site for the toxin appears to facilitate its transmembrane movement. The heat-labile enterotoxin of E. coli is very similar to cholera toxin in both form and function and can also use GM1 as a cell surface receptor. The potent neurotoxin, tetanus toxin, has a high affinity for gangliosides GD1b and GT1b and binds to neurons which contain these gangliosides. It is not yet clear whether these gangliosides are the physiological receptors for tetanus toxin. By applying the techniques that established GM1 as the receptor for cholera toxin, the role of gangliosides as receptors for tetanus toxin as well as physiological effectors may be elucidated.
 ...
PMID:Role of membrane gangliosides in the binding and action of bacterial toxins. 675 18

Blockade of adenosine A2 receptors has been shown to significantly reduce the level of tetanus-induced long-term potentiation in area CA1 of rat hippocampus [Kessey K. et al. (1997) Brain Res. 756, 184-190; Sekino Y. et al. (1991) Biochem. biophys. Res. Commun. 181, 1010-1014]. In the present study, the effects of A2 receptor activation and blockade on the modulation of normal synaptic transmission and tetanus-induced long-term potentiation were examined at the Schaffer-CA1 synapse in rat hippocampal slices. A2 receptor activation reversibly enhanced synaptic transmission evoked by low-frequency test pulses as measured by the dendritic field excitatory postsynaptic potential. In the presence of A1 receptor blockade, A2 activation further enhanced the excitatory postsynaptic potential, while A2 receptor blockade resulted in a reversible decrease of the excitatory postsynaptic potential. The A2a receptor agonist, CGS21680, had no effect on the excitatory postsynaptic potential, suggesting that tonic activation of A2b receptors contributes to synaptic transmission under normal physiological conditions. Furthermore, we investigated the contribution of A2 receptors to the level of tetanus-induced long-term potentiation. Under control conditions, a single tetanus potentiated the excitatory postsynaptic potential by 63.5% relative to baseline 30 min post-tetanus. In contrast, tetanus-induced long-term potentiation during A2 blockade was 21.3%. A2 receptor activation increased the level of tetanus-induced long-term potentiation to 90.2%. Because A2 receptors are known to stimulate cyclic-AMP accumulation, the possible involvement of cyclic-AMP was examined. Forskolin, a direct adenylate cyclase activator, and 8-bromo-cyclic-AMP, a membrane-permeable analog of cyclic-AMP, were able to reconstitute tetanus-induced long-term potentiation during A2 receptor blockade; however, the inactive analog 1,9-dideoxyforskolin had no effect, indicating that the effects of A2 activation on synaptic transmission were mediated largely through the regulation of intracellular cyclic-AMP. Because A1 receptors exert an opposing effect on synaptic transmission relative to A2 receptors, these results suggest that the stoichiometry of A1 versus A2 receptor activation appears to play an important role in the modulation of normal synaptic transmission and long-term potentiation in the CA1 region of the hippocampus.
 ...
PMID:Adenosine A2 receptors modulate hippocampal synaptic transmission via a cyclic-AMP-dependent pathway. 952 62

NAVA's acellular pertussis vaccine is based on highly purified pertussis toxin (PT) inactivated with H(2)O(2). PT was analysed using advanced biochemical methodology including mass spectroscopy (LC/MS), yielding mass and peptide mapping information on the subunits. Pertactin, adenylate cyclase, and Fim 1, 2 were below detection levels and only trace amounts of filamentous haemagglutinin (FHA) have been identified as a minor impurity. The vaccine does not induce anti-FHA antibodies during the course of a 3-dose primary immunization series in infants. B and T cell epitopes are preserved to a higher extent after H(2)O(2)detoxification when compared with chemical inactivation with formaldehyde, thus providing new information explaining why vaccines employing formaldehyde detoxified PT may need additional pertussis components added to induce high levels of protection. Anti-PT antibodies generated by NAVA diphtheria, tetanus, and acellular pertussis vaccine (DTaP) showed a positive correlation with protection against WHO-defined pertussis. The safety profiles for these vaccines showed low reactogenicity with no serious adverse events due to the vaccines.
 ...
PMID:DTaP vaccines from north american vaccine (NAVA): composition and critical parameters. 1060 Jan 91

Presence of antibody to adenylate cyclase toxin (ACT) has been noted following Bordetella pertussis infection. Because ACT is not presently in any acellular pertussis vaccines, it has been considered as a possible antigen to use in B. pertussis diagnostic enzyme-linked immunosorbent assay (ELISA) studies. We determined antibody to B. pertussis ACT by ELISA and Western blot tests in serum samples obtained from unvaccinated children, from children vaccinated with several diphtheria and tetanus toxoid vaccines (DTP vaccines), from children vaccinated with vaccines containing acellular pertussis components in combination with diphtheria and tetanus toxoids (DTaP vaccines), and from children and adults with pertussis. Primary infections with either B. pertussis or Bordetella parapertussis stimulated a vigorous antibody response to ACT. In contrast, patients in whom DTP and DTaP vaccines failed had minimal ACT antibody responses. The lack of a significant ACT antibody response in children in whom the vaccine failed is of interest but would seem to preclude the use of ACT in diagnostic tests.
 ...
PMID:Determination of serum antibody to Bordetella pertussis adenylate cyclase toxin in vaccinated and unvaccinated children and in children and adults with pertussis. 1476 42


1 2 Next >>