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 B subunit of cholera toxin, which binds to ganglioside GM1, enhanced DNA synthesis in rat hepatocytes in primary culture induced by insulin and/or epidermal growth factor. The effect was dose-dependent, and whole cholera toxin, activating adenylate cyclase, showed a higher effect than the B subunit alone. The B subunit acted additively with other agents that also increase cyclic AMP levels. A competitive antagonist of cyclic AMP could not suppress the effect of the B subunit completely. These data suggest that the effect is independent of the cyclic AMP signal pathway, and that GM1 plays a role in hepatocyte proliferation.
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PMID:The B subunit of cholera toxin enhances DNA synthesis in rat hepatocytes induced by insulin and epidermal growth factor. 184 42

In a previous study, we demonstrated that cholera toxin-A subunit, as well as the whole toxin, selectively blocks opioid-induced prolongation of the Ca2+ component of the action potential duration (APD) in dorsal root ganglion (DRG) neurons, indicating mediation of this excitatory effect by Gs-linked opioid receptors. The present study shows that pretreatment of DRG neurons with the B subunit of cholera toxin (1-10 ng/ml; greater than 15 min) can also block mu/delta and kappa opioid-induced APD prolongation, but not shortening. Since the B subunit binds selectively to GM1 ganglioside located on the cell surface, these results suggest that this ganglioside may regulate Gs-linked excitatory opioid receptor functions in DRG neurons. Possible contamination of purified B subunit preparations of cholera toxin with traces of the more potent A subunit was eliminated by heating the stock solution to 56 degrees C for 20 min. Exposure of DRG neurons to an affinity-purified anti-GM1 antiserum also blocked opioid-induced APD prolongation, providing further evidence that GM1 ganglioside may play an essential role in excitatory opioid modulation of the action potential of these cells. The blockade by cholera toxin-B subunit and anti-GM1 antibodies of opioid-induced APD prolongation is best accounted for by the following hypothesis: CTX-B interferes with an endogenous GM1 ganglioside component of the excitatory, but not inhibitory, opioid receptor complex on DRG neurons that may allosterically regulate coupling of the receptors via Gs to adenylate cyclase/cyclic adenosine monophosphate-dependent ionic conductances.
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PMID:Cholera toxin-B subunit blocks excitatory effects of opioids on sensory neuron action potentials indicating that GM1 ganglioside may regulate Gs-linked opioid receptor functions. 198 Nov 60

The effects of daily treatment with GM1 ganglioside (30 mg/kg s.c.) from birth to day 30, on striatal pre- and postsynaptic markers of the dopaminergic system in euthyroid- and 32 day-old hypothyroid rats were studied. The purpose was to assess whether GM1 could prevent the extensive, hypothyroidism-provoked impairment of dopaminergic neurotransmission. Neonatal administration of GM1 well counteracted the hypothyroidism-related deficits in striatal synaptosomal uptake of [3H]dopamine and in membrane binding of [3H]tyramine, a putative marker for the vesicular carrier of dopamine. In the hypothyroid striatum, the decrease of concentrations of DOPAC and HVA, the loss of [3H]SCH-23,390-labelled D1-receptors and the decrease of basal- or dopamine-stimulated, D1-mediated activity of adenylate cyclase were not prevented by GM1. Although somatic and neurobehavioural aberrations of hypothyroids were not at all or only partially ameliorated, a slight improvement of the thyroid status was suggested by less decreased levels of serum thyroxine (T4) after treatment with GM1. The ganglioside-driven selective recovery of the transport and storage process of [3H]dopamine might result either from a chronically-exerted stimulation by GM1 on the NA/K- and Mg-ATPase activities, thus reflecting on the ATPase-dependent neuronal and vesicular transport processes of dopamine or from a GM1-promoted maturation of the otherwise retarded functionality of dopaminergic nerve endings in the neonatal hypothyroid striatum.
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PMID:Dopaminergic dysfunction in neonatal hypothyroidism: differential effects of GM1 ganglioside. 214 73

The use of the B subunit of cholera toxin, a protein that binds specifically to ganglioside GM1, has provided a new paradigm for studying physiological functions of ganglioside GM1. The B subunit inhibited the growth of rat glioma C6 cells that had been pretreated with ganglioside GM1. In some preparations of the B subunit, the inhibition was independent of adenylate cyclase activation and was due to the binding of the B subunit to ganglioside GM1 inserted onto the cell surface. However, in other preparations of the B subunit, there was an additional inhibitory effect due to small contaminations with the A subunit, which caused increases in intracellular cyclic adenosine monophosphate (cAMP) levels and concomitant growth inhibition. This vanishingly small contamination with the A subunit could not be detected by conventional protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis but could be measured utilizing a sensitive adenylate cyclase activation assay. Thus caution must be used to ensure that any biological effects of the B subunit are not due to contaminating A subunit and are due solely to the binding of the B subunit to ganglioside GM1 exposed on the cell surface. This is especially important in cyclic nucleotide-sensitive systems.
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PMID:Cautionary note on the use of the B subunit of cholera toxin as a ganglioside GM1 probe: detection of cholera toxin A subunit in B subunit preparations by a sensitive adenylate cyclase assay. 215 74

GM1 (II3Neu5Ac-GgOse4Cer)-oligosaccharide was prepared from the ganglioside by ozonolysis and alkaline fragmentation, reductively aminated and coupled to the heterobifunctional cross-linker succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate. The resulting derivative reacted with free sulfhydryl groups and readily cross-linked to cell surface components on rat glioma C6 cells which are GM1-deficient. Attachment of the GM1-oligosaccharide derivative, which was monitored by increased binding of 125I-cholera toxin to the cells, was both time- and concentration-dependent. Prior treatment of the cells with dithiothreitol enhanced the attachment by generating additional free sulfhydryl groups. The affinity of cholera toxin for cells treated with the GM1-oligosaccharide derivative or with GM1 was similar. The nature of the newly generated toxin receptors was determined by Western blotting. Membranes from derivatized cells were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the resolved components were electrophoretically transferred to a nitrocellulose sheet which was overlain with 125I-cholera toxin. The toxin bound to a wide variety of membrane proteins, most of which were trypsin-sensitive. No such binding was observed using membranes from control cells. Although the GM1-neoganglioproteins newly generated on the surface of rat glioma C6 cells readily bound cholera toxin, the cells did not become more responsive to the toxin as measured by increased production of cyclic AMP or activation of adenylate cyclase. In contrast, cells exposed to GM1 became highly responsive to the toxin. Thus, neoganglioproteins on the cell surface appear to behave as nonfunctional receptors for cholera toxin.
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PMID:Generation of cell surface neoganglioproteins. GM1-neoganglioproteins are non-functional receptors for cholera toxin. 215 9

Ganglioside (GM1) treatment of CD4+ human CEM lymphoma cells stimulated transient phosphoinositide (PI) breakdown, production of inositol phosphates (IP), protein phosphorylation and rapid decrease of CD4 surface expression. A comparison between the actions of GM1 and other agents that affect these signal transduction pathways demonstrated a distinct mechanism for GM1-induced decrease of CD4. GM1 stimulated both phospholipase C activity and protein phosphorylation but had no effect on either cellular cAMP levels or tyrosine kinase activity. Phorbol myristate acetate (PMA) stimulated protein phosphorylation and caused a significant decrease in surface display of CD4. Both of these processes were blocked by pretreating cells with the protein kinase C (PKC) inhibitor H7. These results demonstrate that GM1 stimulates PI turnover and induces a rapid decrease of CD4 surface expression by processes that do not activate adenylate cyclase or tyrosine kinase. They further demonstrate that the mechanism for GM1-induced decrease of CD4 is distinct from the CD4 internalization processes mediated by PKC activity.
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PMID:Transmembrane signalling associated with ganglioside-induced CD4 modulation. 217 87

Cholera toxin (CT) is a potent stimulator of IgA responses when administered orally and has been shown to promote IgA responses to a second protein such as keyhole limpet haemocyanin (KLH) if this is fed simultaneously. In this paper we show that whilst feeding 5 mg KLH with either 0.5 micrograms CT or 10 micrograms B subunit fails to stimulate a mucosal IgA response to KLH, feeding 0.5 microgram CT and 10 micrograms B subunit together with 5 mg KLH produces a local IgA anti-KLH response as great as that produced by 10 micrograms of whole CT. In addition to stimulating IgA responses in the lamina propria, preliminary results indicate that cellular responses are also stimulated, as we have demonstrated KLH antigen-driven proliferation of cells isolated from groups of mice fed either 10 micrograms CT + 5 mg KLH or 0.5 micrograms CT + 10 micrograms CTB + 5 mg KLH but not mice fed KLH alone or with either 10 micrograms CTB or 0.5 micrograms CT. These results indicate that the mucosal adjuvant action of CT is due to a synergistic effect involving both the GM1 binding of the B subunit and adenylate cyclase activation by the A subunit.
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PMID:Whole cholera toxin and B subunit act synergistically as an adjuvant for the mucosal immune response of mice to keyhole limpet haemocyanin. 233 68

Gangliosides (GM1, GT1b, GD3) were incorporated in bovine thyroid plasma membranes using the nonspecific lipid transfer protein from beef liver. The transfer of GT1b or GD3 in the presence of 16 units of transfer protein was twice as high as that of GM1. However, taking into account the spontaneous exchange (approximately 8% for GT1b or GD3 and 1% for GM1) the transfer protein seemed to be more effective for GM1. Incorporation of these gangliosides in bovine thyroid plasma membranes caused a concentration dependent inhibition of the TSH-stimulated adenylate cyclase activity. The forskolin-stimulated adenylate cyclase activity was not significantly affected by ganglioside modification of the plasma membranes, indicating that the gangliosides do not act at the level of the catalyst of adenylate cyclase. Binding experiments on the other hand revealed that TSH binding to bovine thyroid plasma membranes was inhibited with the same order of efficacy (GT1b greater than GD3 greater than GM1) and to the same extent as their inhibitory effect on TSH stimulation. Therefore, this indicates that the ganglioside induced drop in TSH binding might be an important factor in the decrease in TSH-stimulated adenylate cyclase activity. Incorporation of GT1b or GD3 (approximately 11 nmol) in bovine thyroid plasma membranes, however, also induced a substantial decrease in cholera toxin-stimulated adenylate cyclase activity (approximately 30%) and to a lesser degree a decrease in NaF-stimulated activity (approximately 17%), whereas GM1 incorporation did not significantly affect these stimulated activities. These latter inhibitory effects were paralleled by changes in fluorescence steady-state anisotropy: GT1b modification of the plasma membranes provoked a slight increase in TMA-DPH anisotropy, whereas the anisotropy of DPH was substantially enhanced after incorporation of GD3 or GT1b. These results suggest that gangliosides might also interfere with the coupling between the alpha-subunit of the stimulatory GTP-binding regulatory protein and the catalyst of the adenylate cyclase system by affecting the membrane fluidity.
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PMID:Modification of the adenylate cyclase activity of bovine thyroid plasma membranes by manipulating the ganglioside composition with a nonspecific lipid transfer protein. 233 19

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

Cholera toxin (CT) irreversibly ADP-ribosylates and activates the nucleotide-stimulatory (Ns) subunit of adenylate cyclase in many tissues, thereby eliciting cyclase-dependent functions. Although earlier studies performed at room temperature could not demonstrate CT-stimulated water transport in toad urinary bladder, subsequent work in other tissues has emphasized the need for incubation at 35-37 degrees C to effect ribosylation and the subsequent physiological effects. We found that incubating tissues with amphibian culture media, rather than Ringer solution, maintained tissue viability at this higher temperature and permitted prolonged incubation with CT. At 37 degrees C, in the presence of 0.1 mM phosphodiesterase inhibitor (1-methyl-3-isobutylxanthine, MIX), 0.2-200 nM mucosal CT caused a dose-dependent but submaximal enhancement of water flux and urea transport. Elimination of MIX from the bath diminished subsequent CT-induced stimulation, supporting a role for adenosine 3',5'-cyclic monophosphate (cAMP) as mediator of the CT effect. The increased water flow was stable for greater than 1 h after removal of CT from the bath, consistent with irreversible stimulation of the cyclase. Mucosal CT stimulated transport to a greater degree than serosal CT, paralleling the pattern seen in the intestine, which is compatible with passage of the toxin's a subunit across the cell to the serosal membrane cyclase. Exposure of the tissue's mucosal surface to GM1 ganglioside, (the natural receptor for the CT b subunit) yielded maximal stimulation of water flow and near-maximal urea transport, presumably by increasing CT's binding to the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholera toxin enhances adenylate cyclase-dependent transport in toad urinary bladder. 243 87


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