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)

The classification of muscarinic receptors into M1 and M2 subtypes and the involvement of guanine nucleotide binding proteins (G-proteins) as major mediators of receptor information transduction in the cholinergic and other neurotransmitter systems have prompted us to undertake studies both at receptor and postreceptor levels that may shed light on the importance of these new findings to the pharmacotherapy of manic-depressive illness and of extrapyramidal syndromes. We searched for patterns of muscarinic selectivity among the commonly used anticholinergics (biperiden, procyclidine, trihexyphenidyl, benztropine, and methixen) through radioligand receptor studies in various rat tissues. The drugs showed a range of selectivity, from the totally nonselective methixen to the highly M1-selective biperiden. Sinus arrhythmia measurements were undertaken in psychiatric patients treated with different antiparkinsonian anticholinergics. The extent of sinus arrhythmia suppression was inversely correlated with the degree of M1 selectivity of the drugs used, advocating the use of M1-selective antiparkinsonian anticholinergics like biperiden in the treatment of extrapyramidal side effects. The implications of muscarinic receptor subclassification were further extended to include postreceptor phenomena. We have directly studied G-protein function by measuring cholinergic agonist-induced increases in guanosine triphosphate (GTP) binding to these proteins. This cholinergic agonistic effect was shown to be exerted by G-proteins other than Gs (the adenylate cyclase stimulatory G-protein), i.e., Gi (the adenylate cyclase inhibitory G-protein) or Gp [the G-protein activating phosphatidylinositol (PI) turnover], as ribosylation by pertussis toxin abolished this cholinergic effect, whereas it was unaffected by cholera toxin. Pertussis toxin-blockable, carbamylcholine-induced increases in GTP binding capacity were found to be mediated through M1 muscarinic receptors, as M1-selective antagonists were 100-fold more effective than M2 selective antagonists in blocking carbamylcholine effects. Moreover, carbamylcholine effect was exclusively detected in tissues predominantly populated by M1 receptors. Our results thus suggest that carbamylcholine-induced increases in GTP binding are exerted through M1 receptors interacting with Gp. At therapeutically efficacious concentrations, lithium completely blocked carbamylcholine-induced increases in GTP binding capacity in both in vitro and in vivo experiments.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic receptor subclassification and G-proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics. 256 9

Subtypes of muscarinic cholinergic receptors have been proposed to exist, but the biochemical responses mediated by the putative subtypes are unknown. In the present study, muscarinic receptor-mediated phosphoinositide breakdown and inhibition of adenylate cyclase activity were characterized in rat brain as well as rat parotid and heart. To study whether these responses are mediated by separate subtypes of muscarinic receptors, the potencies of agonists and antagonists were determined in both assays. Antagonist potencies were calculated by Schild analysis. In the brain, the putatively selective muscarinic receptor antagonist, pirenzepine, exhibited Ki values of 21 nM in the assay of phosphoinositide breakdown and 310 nM in the assay of adenylate cyclase activity. Similarly, using radioligand binding techniques, it distinguished two binding sites with Kd values of 12 and 168 nM. The antagonist, atropine, on the other hand, was equipotent in the two biochemical assays and the radioligand binding assay with Ki values of approximately 1 to 2 nM. In peripheral tissues with robust muscarinic receptor-mediated phosphoinositide (parotid) and adenylate cyclase (heart) responses, pirenzepine exhibited a similar selectivity (19-fold) for the phosphoinositide assay that was seen in the brain, but it was 6- to 7-fold less potent in both peripheral tissues than in the central nervous system. In addition, the potencies of pirenzepine in binding and functional studies in each tissue were not as well correlated as in the brain. Atropine and other antagonists were 4- to 9-fold selective for inhibiting oxotremorine-stimulated phosphoinositide breakdown in the peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pirenzepine distinguishes between muscarinic receptor-mediated phosphoinositide breakdown and inhibition of adenylate cyclase. 257 30

It was found that serotonin relaxed desensitization and decreased acetylcholine-induced potassium current. Effects of serotonin were connected with serotonin-activated adenylate cyclase, adenosine 3':5'-cyclic monophosphate (cAMP) and phosphorylation of muscarinic receptor proteins by cAMP-dependent protein kinase.
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PMID:[Serotonin modulation of the muscarinic cholinoreceptor status of the neurons in the mollusk Planorbarius corneus]. 260 68

The effects of isoprenaline and carbachol on the delayed after-depolarization (DAD) induced by acetyl strophanthidin of 2.0 x 10(-7) mol/L were observed in sheep cardiac Purkinje fibers. The amplitude of DAD was enhanced by isoprenaline (1.0--3.0 x 10(-8) mol/L) in a dose-dependent manner and the triggered arrhythmia was induced. Carbachol of 2.0 x 10(-6) mol/L alone had no effect on the amplitude of DAD. When the DAD was enhanced by isoprenaline or the triggered arrhythmia was induced, the same concentration of carbachol could decrease the amplitude of DAD significantly and abolish the triggered arrhythmia. However, carbachol did not attenuate the amplitude of the DAD enhanced by high concentration of calcium, aminophylline or histamine. The results suggest that carbachol can antagonize the enhancement of the DAD caused by isoprenaline. This effect is possibly mediated by activation of the muscarinic receptor, which in turn causes a decrease in the adenyl cyclase activity elevated by the activation of the beta-receptor in the membrane.
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PMID:[Effects of isoprenaline and carbachol on delayed after-depolarization in myocardium]. 260 47

In IMR32 neuroblastoma cells, the two adenosine receptor agonists N6-R-phenylisopropyladenosine and 5'-N-ethylcarboxamidoadenosine dose-dependently stimulated membrane adenylate cyclase activity with potencies consistent with the presence of adenosine receptors of the A2-subtype. The S enantiomer of N6-R-phenylisopropyladenosine induced a significantly lower stimulation of adenylate cyclase, accordingly to its lower ability to activate adenosine receptors. These effects were selectively counteracted by the adenosine receptor antagonist theophylline and, conversely, were not affected by the A1-adenosine receptor selective blocker 8-cyclopentyl-1,3-dipropylxanthine. No adenosine receptors belonging to the A1-subtype seem, therefore, to be present in this cell line, as also shown by the lack of inhibitory activity of N6-R-phenylisopropyladenosine on both basal and forskolin-stimulated adenylate cyclase activity. Activation of A2-receptors did not modify intracellular basal calcium levels, did not influence calcium influx through voltage-dependent calcium channels and did not modify calcium influx and redistribution induced by muscarinic receptor activation. Prolonged exposure of cells to either N6-R-phenylisopropyladenosine or 5'-N-ethylcarboxamidoadenosine was associated with a small but significant degree of morphological differentiation, comparable to that induced by dibutyryl cAMP, and therefore presumably related to the prolonged increase of intracellular cAMP levels elicited by the two adenosine agonists. After cellular differentiation induced with either dibutyryl cAMP or 5-bromodeoxyuridine, a selective desensitization of A2-receptor stimulated adenylate cyclase activity was found.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptors linked to adenylate cyclase activity in human neuroblastoma cells: modulation during cell differentiation. 277 Oct 50

The binding properties of a series of muscarinic antagonists were compared with their ability to antagonize muscarinic receptor mediated inhibition of adenylate cyclase activity in homogenates of the corpus striatum and heart of rats. When measured by the competitive inhibition of the binding of the muscarinic antagonist N-[3H]methylscopolamine, the binding properties of selective muscarinic antagonists in the corpus stratum and cerebral cortex were consistent with a model incorporating a minimum of three populations of muscarinic receptors, a high affinity site for pirenzepine (M1), a high affinity site for AF-DX 116 [11] [2-[ (diethylamino)methyl]-1-piperidinyl] acetyl] -5, 11-dihydro-6H-pyrido [2,3-b] 1,4] benzodiazepine-6-one (M2) and a third population (non-Ml, non-M2 sites) displaying low affinity for the latter antagonists. The results of similar experiments on the heart showed that this tissue contained a uniform population of M2 muscarinic receptors. The binding properties of the M2 receptor in cerebral cortex and corpus stratum were also investigated directly in antagonist [3H] AF-DX 116 competition experiments and, although the high affinity AF-DX 116 site in brain (M2) exhibited selectivity for the cardioselective antagonists AF-DX 116 and gallamine, some differences were noted between M2 sites in brain and heart. The muscarinic adenylate cyclase response in the corpus striatum was relatively insensitive to the M2 selective antagonists AF-DX 116 and gallamine as well as the M1 selective antagonist pirenzepine, suggesting that non-M1, non-M2 sites inhibit adenylate cyclase activity in the corpus striatum. In contrast, the effects of muscarinic antagonists on the muscarinic adenylate cyclase response in the heart were consistent with the postulate that M2 receptors inhibit adenylate cyclase activity in this tissue.
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PMID:Coupling of subtypes of the muscarinic receptor to adenylate cyclase in the corpus striatum and heart. 281 Jan 16

Acetylcholine inhibits FSH-induced cAMP accumulation in cultured Sertoli cells from immature hamsters. This action of acetylcholine is mimicked by muscarinic cholinergic agonists with a rank order of carbachol greater than acetylcholine greater than arecoline greater than pilocarpine. The carbachol-induced inhibition of stimulated cAMP accumulation is blocked by atropine greater than pirenzepine but not by d-tubocurarine, indicating an apparent muscarinic receptor similar to that found in other peripheral tissues. The fact that pirenzepine is less effective as an inhibitor of the carbachol effect than atropine further defines the muscarinic effect as of the M2 subtype. The ability of carbachol to inhibit FSH-induced cAMP accumulation is blocked by pertussis toxin, which inhibits the action of the Ni inhibitory transducer of adenylate cyclase. These data indicate that cultured Sertoli cells from immature hamsters contain an M2 type muscarinic cholinergic receptor that is negatively coupled to the adenylate cyclase system through the inhibitory Ni transducer.
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PMID:Cholinergic inhibition of cAMP accumulation in Sertoli cells cultured from immature hamsters. 282 40

In the presence of Ro 20-1724, a selective inhibitor of cyclic nucleotide phosphodiesterase, carbamylcholine increases cAMP and cGMP levels in human thyroid cells in primary culture. The increase of cAMP exhibited at concentrations of carbamylcholine between 10 fM and 10 pM, is dose- and time-dependent, it is maximum after 30 min and is abolished after 60 min. At higher carbamylcholine concentration (10 microM), cAMP increases rapidly, becoming maximum after 15 min, but returns to unstimulated values after 30 min. The increase of cGMP is also dose-dependent (0.1 nM-10 microM); it reaches the maximum after 30 min and returns to unstimulated values after 120 min. A significant increase of phosphodiesterase activity is observed at 10 microM carbamylcholine. Atropine, a muscarinic receptor antagonist, blocks carbamylcholine effects on both cAMP and cGMP production without affecting the thyrotropin-induced cAMP accumulation. Hexamethonium, a nicotinic receptor antagonist does not affect the cholinergic effects. In the presence of Ro 20-1724, 10 microM carbamylcholine significantly inhibits the effect of thyrotropin on cAMP production, while the combined addition of low doses of carbamylcholine and thyrotropin (0.1 nM and 10 pM, respectively) results in an additive effect on cAMP levels. Inhibition of thyrotropin activity on cAMP production, similar to that exerted by 10 microM carbamylcholine is produced by increasing free intracellular calcium; this inhibition is relieved by using a calmodulin-sensitive phosphodiesterase inhibitor, M and B 22948 at 50 microM dose. High concentrations (10 microM) of carbamylcholine increase the adenylate cyclase activity, without any significant effect on the thyrotropin-induced activation of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholinergic control of cyclic nucleotide metabolism in human thyroid cells. 282 57

The effect of vasoactive intestinal polypeptide (VIP) on the 3'-5'-cyclic adenosine monophosphate (cAMP) generating system in membrane particles of rat portal vein was studied. In the presence of 10 microM GTP, VIP increased the concentration of cAMP in a dose-dependent manner. The removal of endothelium had no effect on cAMP production elicited by VIP. alpha- and beta-adrenergic as well as muscarinic receptor blocking agents did not inhibit VIP-dependent cAMP increase. Also various peptides, structurally analogous to VIP or active on portal vein smooth muscle, had no effect on cAMP production elicited by VIP. The present data, combined with those reported in the literature of an active relaxation of portal vein smooth muscle by VIP, suggest the existence of functionally active VIP receptors coupled to the adenylate cyclase system in the rat portal vein.
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PMID:Vasoactive intestinal polypeptide-sensitive cyclic adenosine monophosphate generating system in the rat portal vein. 283 24

Although desensitization of the beta AR-coupled adenylate cyclase system has been stressed in this chapter, it appears to be a useful model. Carbachol induces sequestration of muscarinic receptors in several cell lines. More recently, agonist-mediated phosphorylation of muscarinic receptors in chick heart has been observed. Based on the predicted amino acid sequence from the recently cloned cDNA, the muscarinic receptor resembles beta AR and rhodopsin with seven membrane-spanning regions and several potential phosphorylation sites in the carboxy-terminal region. Thus, receptor phosphorylation and sequestration may be a general mechanism of desensitization.
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PMID:Receptor desensitization. 284 13


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