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)

We investigated the effects of [D-Ala2,D-Leu5]enkephalin (DADLE). [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO), [D-Pen2,D-Pen5]enkephalin (DPDPE) (0.01-1 microM) and bremazocine (0.001-0.3 microM) on the electrically evoked release of radiolabelled neurotransmitters and on the dopamine (DA)-stimulated cyclic AMP efflux from superfused rat brain slices. The differential inhibitory effects of these agonists on the evoked neurotransmitter release indicate that the opioid receptors mediating presynaptic inhibition of [3H]noradrenaline (NA, cortex), [14C]acetylcholine (ACh, striatum) and [3H]DA (striatum) release represent mu, delta and kappa receptors, respectively. In agreement with this classification, preincubation (60 min) of the slices with the delta-opioid receptor-selective irreversible ligand, fentanyl isothiocyanate (FIT, 0.01-1 microM), antagonized the inhibitory effects of DADLE and DPDPE on striatal [14C]ACh release only. On the other hand, the D-1 DA receptor-stimulated cyclic AMP efflux from striatal slices appeared to be inhibited by activation of mu as well as of delta receptors. In this case, the reversible mu antagonist, naloxone (0.1 microM), fully antagonized the inhibitory effect of the mu agonist, DAGO, without changing the effect of the delta agonist DPDPE but was ineffective as an antagonist in slices pretreated with FIT (1 microM). The inhibitory effect of DAGO on the electrically evoked [3H]NA release was antagonized by naloxone whether the receptors were irreversibly blocked by FIT or not. These data not only further support the existence of independent presynaptic mu-, delta- and kappa-opioid receptors in rat brain but also evidence strongly that mu and delta receptors mediating the inhibition of DA-sensitive adenylate cyclase could share a common binding site (for naloxone and FIT) and, therefore, may represent constituents of a functional opioid receptor complex.
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PMID:Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate. 290 10

Nicotine and muscarine caused the transient increase in cAMP and cGMP efflux from dog adrenal glands followed by a small but lasting increase in the nucleotide efflux. The initial increase preceded catecholamine (CA) release and the latter slowly developed. Nicotine and muscarine caused the maximal increase of cAMP and cGMP levels in adrenal medulla 15 sec after the treatment, and these effects were antagonized by hexamethonium and atropine, respectively. Hexamethonium in combination with atropine, verapamil and an omission of Ca2+ in the medium prevented ACh from producing the increase in cyclic nucleotide efflux and CA release. Reintroduction of Ca2+ (1.3 mM) in fluid after perfusion with Ca2+ and Mg2+-free fluid caused the transient increase in cyclic nucleotide efflux and CA release. Adenylate cyclase activity in adrenal medulla was activated by Ca2+. These results may suggest that cAMP formation was increased by activation of adenylate cyclase as a result of increased influx of Ca2+ when adrenal medulla were stimulated.
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PMID:Stimulation-evoked cyclic nucleotides efflux from isolated perfused dog adrenals and possible involvement of calcium. 300 46

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.
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PMID:Pertussis toxin-insensitive phosphoinositide hydrolysis, membrane depolarization, and positive inotropic effect of carbachol in chick atria. 304 Feb 95

We have investigated whether muscarinic receptors modulate the release of [3H]ACh elicited by secretagogues that act by different mechanisms in rat cerebral cortical synaptosomes. Oxotremorine (10 microM) reduced the calcium-dependent [3H]ACh release induced by mild K+-depolarization (10 and 15 mM K+), but not that by higher K+ concentrations. The ACh-release induced by A23187 (0.2-5 micrograms/ml), liposomes laden with 113 mM CaCl2, or 4-aminopyridine (1-10 mM) was not modulated by oxotremorine. Ouabain (100 microM)-induced release of [3H]ACh was reduced by oxotremorine in normal but not calcium-free KR, indicating that extracellular calcium-uptake but not Na+, K+-ATPase activity may be necessary for release-modulation. With respect to possible second messenger systems, dibutyrylcyclic AMP (0.1-2 mM), dibutyrylcyclic GMP (0.1-2 mM), forskolin (100 microM), and phorbol ester (0.3-3 micrograms/ml) were without effect on release or release-modulation. These results are consistent with an involvement of K+-channels and voltage-sensitive calcium-channels in the muscarinic release-inhibition process. They argue against an involvement of Na+, K+-ATPase, adenylate cyclase, guanylate cyclase, and phosphatidylinositol turnover in the release-modulation process.
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PMID:Effects of different secretagogues and intracellular messengers on the muscarinic modulation of [3H]acetylcholine release. 312 25

Isoproterenol activates adenylate cyclase indirectly via the beta-receptors. Forskolin, on the other hand, directly activates the adenylate cyclase. Both compounds can induce slow action potentials (APs) in isolated guinea pig papillary muscles, consistent with their ability to activate adenylate cyclase. Acetylcholine (ACh), 1-10 microM, depressed or abolished slow APs induced by isoproterenol or forskolin. There was no difference between the forskolin- and isoproterenol-induced slow APs with regard to their sensitivity to ACh. Similar results were obtained in cultured embryonic chick heart cells. We conclude that forskolin induces slow APs that are essentially the same as those induced by isoproterenol, and that ACh action on depressing slow APs must be either directly on the adenylate cyclase complex and/or on another step entirely (e.g., mediated through increased cGMP.
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PMID:Cholinergic attenuation of the electrophysiological effects of forskolin. 370 Jul 74

The stimulation of GTP hydrolysis has been proposed as a mechanism by which hormones inhibit receptor-coupled adenylate cyclase activity. The present study attempts to verify whether this mechanism is also operative in transmitter-mediated receptor-coupled attenuation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] located in synaptic plasma membrane preparations. As a model, we used the inhibition of adenylate cyclase activity by muscarinic receptor activation in rat striatum. This striatal preparation contains high-affinity GTPase (EC 3.6.1-) activity which is stimulated when the recognition site for muscarinic agonists is occupied. Acetylcholine (ACh), but not nicotine, increases the Vmax of the high-affinity GTPase, and the stimulatory effect is antagonized by atropine but not by d-tubocurarine. The rank order of potency of various cholinergic agonists to stimulate GTPase correlates with their ability to inhibit adenylate cyclase activity of striatal membranes. Pre-exposure of striatal membranes to guanosine-5'-O-(3-thiotriphosphate) causes a parallel decrease in the basal and ACh-stimulated GTPase activities and in the ACh-induced inhibition of adenylate cyclase. Treatment of the membranes with cholera toxin does not affect the ACh-stimulated GTPase activity but amplifies the extent of adenylate cyclase inhibition elicited by the cholinergic agonist. These results indicate that the stimulation of a high-affinity GTPase parallels the inhibitory coupling of central muscarinic receptors to adenylate cyclase.
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PMID:Involvement of a high-affinity GTPase in the inhibitory coupling of striatal muscarinic receptors to adenylate cyclase. 613 2

Methylisobutylxanthine (MIX) augmented contractions and Ca++-dependent action potentials in ventricles isolated from embryonic and hatched chicks. Acetylcholine (ACh) inhibited these effects of MIX. In ventricles from chicks on the 18th incubation day, cyclic AMP content was increased to about 150% of basal after 3 min in 3 X 10(-4) M MIX. ACh (10(-6) M) did not reduce the cyclic AMP accumulation caused by MIX, although the increase in twitch tension was abolished. However, 10(-4) M ACh blocked the MIX-induced increases in both twitch tension and cyclic AMP. We conclude, therefore, that ACh antagonizes the effects of MIX both by blocking the action of elevated cyclic AMP and in higher concentrations, also by inhibiting the accumulation of cyclic AMP. In homogenates of chick ventricles. ACh neither stimulated phosphodiesterase activity nor blocked the inhibition of phosphodiesterase by MIX. Therefore, inhibition of cyclic AMP accumulation by higher concentrations of ACh may result from an inhibition of adenylate cyclase activity. Since neither 10(-6) nor 10(-4) M ACh reduced basal cyclic AMP content, basal adenylate cyclase is presumably not affected by ACh. We speculate that MIX may indirectly increase adenylate cyclase activity by antagonizing an inhibitory effect of endogenous adenosine. Furthermore, ACh may interfere with this effect of MIX, thereby facilitating the inhibition of adenylate cyclase by adenosine.
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PMID:Muscarinic antagonism of the effects of phosphodiesterase inhibitor (methylisobutylxanthine) in embryonic chick ventricle. 616 Feb 37

Acetylcholine inhibits, by 30-40%, the basal adenylate cyclase activity of purified synaptic plasma membranes prepared from rat striatum (EC50 = 3 microM). Cholinergic receptor agonists inhibit this cyclase activity with the following rank order of potency: oxtremorine greater than acetylcholine greater than arecoline greater than methacholine greater than or equal to muscarine greater than or equal to carbachol greater than bethanechol. Nicotine fails to inhibit the cyclase, and d-tubocurarine fails to inhibit the action of cholinergic drugs. In contrast, atropine and scopolamine antagonize the effect of acetylcholine. The enzyme inhibition elicited by acetylcholine requires the presence of GTP, and disappears after intrastriatal injection of kainic acid. From these results, we infer that striatal adenylate cyclase can be modulated by muscarinic receptors.
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PMID:Adenylate cyclase activity of synaptic membranes from rat striatum. Inhibition by muscarinic receptor agonists. 618 35

Various agents which are known to affect intracellular levels of cAMP have been assessed for their ability to induce the release of [3H]acetylcholine ([3H]ACH) from a synaptosomal preparation derived from the guinea-pig ileum myenteric plexus. 8-Bromo-cAMP increased the release of [3H]ACh above basal levels. While 8-bromo-cGMP also increased the release, this nucleotide was far less potent than 8-bromo-cAMP. Comparison of the release caused by the cyclic nucleotides to the release induced by the nicotinic agonist dimethylphenylpiperazinium (DMPP) suggested that there is some relationship, as yet undefined, between the 8-bromo-cAMP-induced and the DMPP-induced release, while no relationship was evident between the release induced by 8-bromo-cGMP and that caused by DMPP. The 8-bromo-cAMP-induced release was Ca2+-dependent. Neither adenosine, clonidine, nor oxotremorine (all of which modulate the nicotinically-induced release) affected the 8-bromo-cAMP-induced release. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine stimulated the release of [3H]ACh as did the adenylate cyclase activator forskolin. The forskolin-induced release was not affected by adenosine, clonidine or oxotremorine. The ability of the modulators to block the nicotinically-induced release but not the release caused by the cyclic nucleotides indicates that the modulation of release evoked by nicotinic activity does not occur at a step involving protein phosphorylation.
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PMID:Stimulation of acetylcholine release from guinea-pig ileal synaptosomes by cyclic nucleotides and forskolin. 620 34

Acetylcholine (ACh, 10(-6) M) had no effect on basal adenylate cyclase activity (3.4 +/- 0.56 pmol cyclic AMP . min-1 . mg wet wt-1), adenosine 3',5'-cyclic monophosphate (cyclic AMP) content (0.88 +/- 0.09 pmol/mg wet wt), or the force of contraction in paced (2.5 Hz) chick embryo right ventricles superfused with Tyrode solution. After 60-180 min of superfusion in the presence of cholera toxin (5 x 10(-6) g/ml), adenylate cyclase activity (1.7 times), cyclic AMP content (2.4 times), and contractility (2.4 times) had increased significantly above basal levels. ACh reversed the positive inotropic effect of cholera toxin but did not change the increased activity of adenylate cyclase and content of cyclic AMP obtained in cholera toxin. Stimulation of adenylate cyclase by isoproterenol (ISO) was inhibited by ACh in the absence and presence of cholera toxin. ACh did not change guanosine 3',5'-cyclic monophosphate (cyclic GMP) content in the absence or presence of cholera toxin. Cholera toxin has actions on chick embryo ventricle similar to those of the beta-adrenergic agonist, ISO, and the phosphodiesterase inhibitor, isobutylmethylxanthine. The ability of ACh to reverse the positive inotropic effect of cholera toxin without preventing the accumulation of cyclic AMP may involve the prevention or reversal of cyclic AMP-dependent phosphorylation. In this regard, reduction of Ca2+ influx through voltage-sensitive membrane channels may be an essential component of muscarinic inhibition.
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PMID:Acetylcholine inhibits positive inotropic effect of cholera toxin in ventricular muscle. 628 67


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