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)

Cyclic GMP (cGMP) has been proposed to be involved in mediating negative inotropic responses to muscarinic agonists in the presence of cyclic AMP (cAMP)-generating agents in the heart. In order to investigate this hypothesis, the effects of the novel cGMP lowering agent, LY83583, on carbachol-induced increases in cGMP levels and decreases in tension were measured in rabbit isolated left atria and right ventricular papillary muscles, in the presence and absence of the adenylate cyclase activator, forskolin. In vehicle-treated preparations, negative inotropic responses to 3 microM carbachol in the presence of 3 microM forskolin were accompanied by significant increases in cGMP levels. Carbachol had no significant effect on forskolin-induced increases in cAMP levels. LY83583 (10 microM) reduced basal tension and basal cGMP levels, and completely abolished carbachol-induced increases in cGMP both in left atria and in papillary muscles. The LY83583 significantly reduced the magnitude of the negative inotropic responses of papillary muscles to carbachol in the presence of forskolin, but had no effect on these responses in left atria. Although a causal relationship has not been established, these data suggest that cGMP may be involved in negative inotropic responses to muscarinic stimulation in the presence of cAMP-generating agonists in ventricular muscle, but not in atria.
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PMID:Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations. 301 20

The effects of isoproterenol, carbachol and other drugs on the cyclic AMP and cyclic GMP levels in tracheal smooth muscles of guinea-pigs of four different ages were investigated. Isoproterenol increased the cyclic AMP level several-fold in tracheal muscles from newborn (1 week) and young (4-7 weeks) guinea-pigs, but it caused less increase in the level in muscles from middle-aged (12 weeks) and old (20-24 weeks) guinea-pigs, although the basal cyclic AMP level at these ages was not significantly lower. The effects of prostaglandin E1 and cholera toxin in increasing the cyclic AMP level were also markedly less in muscle preparations from old guinea-pigs than in those from young ones. The increase in cyclic AMP levels caused by forskolin, an activator of adenylate cyclase did not decrease with age. Carbachol caused a 3- to 4-fold increase in the cyclic GMP level in muscle preparations from newborn and young guinea-pigs and more increase in the cyclic GMP level in preparations from middle-aged and old guinea-pigs. The increases in cyclic GMP level induced by high K+, histamine and sodium nitroprusside also increased with the age of the animals. These results suggest that the changes in the formation of cyclic AMP and cyclic GMP induced by various agents are due to changes at the post-receptor level.
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PMID:Effect of age on the formation of cyclic nucleotides in guinea-pig tracheal smooth muscle in response to pharmacological agents. 301 24

Cat myocardium was used to investigate muscarinic receptor function in atria and ventricles. Carbachol and oxotremorine were used to determine agonist binding to the muscarinic receptors. It was found that carbachol was bound with almost the same characteristics in atria (KdH 1 microM; KdL 150 microM) as in ventricles (KdH 3 microM; KdL 150 microM). However, in the presence of guanylylimidodiphosphate Gpp(NH)p a difference was apparent so that the ventricular curve was shifted to a majority of low affinity sites whereas in atria two affinity sites remained even if the guanine nucleotide concentration was increased to 10 mM. Oxotremorine was bound with almost equal affinity in both atria and ventricles. The addition of Gpp(NH)p left all the receptors in the low affinity state irrespective of receptor localisation. The two agonists were also used to determine inhibition of adenylate cyclase activity. It was shown that the magnitude of adenylate cyclase inhibition was more pronounced in ventricles than in atria whether it was induced by oxotremorine or carbachol. When the effects of muscarinic agonists were determined on phosphatidylinositol metabolism it was shown that carbachol mediated a greater effect in atria than in ventricles. Almost no effect was seen with oxotremorine on phosphatidylinositol breakdown. Pirenzipine binding showed the presence of M1 receptors both in atria and ventricles. On the basis of diversity of muscarinic agonists on function and receptor occupancy it is suggested that heterogeneity exists for muscarinic receptors in both atria and ventricles.
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PMID:Muscarinic receptors in mammalian myocardium: effects of atrial and ventricular receptors on phosphatidylinositol metabolism and adenylate cyclase. 301 67

In the present work, we investigated, by use of forskolin, whether adenosine 3',5'-cyclic monophosphate (cAMP) level and Ca movements were modulated sequentially or in parallel by the activation of the beta-adrenergic receptor in the rat parotid gland. Forskolin-induced [3H]protein secretion was dependent on external Ca, whereas isoproterenol-induced secretion was not. This effect was not due to a requirement of adenylate cyclase for Ca, since the cAMP level increase induced by forskolin was not Ca dependent. Furthermore isoproterenol induced 45Ca efflux, whereas forskolin did not. 45Ca efflux was correlated neither to cAMP nor to secretion, since when there was a massive augmentation of cAMP there was no change in 45Ca efflux, and forskolin, which induced much secretion, was unable to induce Ca efflux. Carbachol potentiated the secretion induced by forskolin in the absence of Ca, whereas it did not potentiate the isoproterenol-induced response. From these results we suggest that beta-adrenergic receptor activation would lead to two parallel events, cAMP accumulation and Ca movements, which together would lead to maximal secretion.
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PMID:Forskolin, a tool for rat parotid secretion studies: 45Ca efflux is not related to cAMP. 302 93

Carbachol is 100 times more potent for inhibiting cyclic AMP formation than for stimulating phosphoinositide (PI) hydrolysis in chick heart cells. To determine whether this reflects differences in agonist affinity of the receptor(s) coupled to the two responses, we measured these functional responses following removal of receptor reserve with propylbenzilycholine mustard (PrBCM). Conditions of PrBCM treatment that led to progressive loss of up to 95% of the [3H]-N-methylscopolamine-binding sites decreased the potency but not the maximal capacity of carbachol to inhibit cyclic AMP formation. In contrast, there was a marked decrease in the maximal PI response to carbachol. The KA for carbachol, calculated by measuring functional responses following receptor inactivation, was similar whether the cyclic AMP or the PI response was examined. These KA values (approximately 40 microM) were similar to the KD calculated by examining carbachol competition for [3H]-N-methylscopolamine-binding sites on the intact cell. PrBCM treatment also decreased the maximal effect of oxotremorine on cyclic AMP formation under conditions in which carbachol remained a full agonist for this response. We interpret our data as indicating that: there is much greater receptor reserve in the coupling of muscarinic receptors to adenylate cyclase than to PI hydrolysis; this, rather than differences in receptor affinity underlies the disparate dose-response relationships for the two responses; and differences in the effects of weak agonist on the two responses may also reflect differences in receptor reserve. We suggest that muscarinic receptors with the same affinity for carbachol interact with different efficiency with the transducers (Gi and Gx) that regulate adenylate cyclase and phospholipase C.
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PMID:Differences in muscarinic receptor reserve for inhibition of adenylate cyclase and stimulation of phosphoinositide hydrolysis in chick heart cells. 302 10

Dopamine inhibits and serotonin stimulates adenylate cyclase activity in a neuroblastoma X Chinese hamster brain explant cell line (NCB-20). The inhibition of cyclic AMP accumulation by dopamine was blocked by pretreatment of the cells with pertussis toxin. Carbachol and bradykinin stimulated the accumulation of water-soluble inositol phosphates whereas thyrotropin-releasing hormone, vasopressin, neurotensin, and phenylephrine were without effect. Dopamine and serotonin had no significant effect on carbachol-induced phosphoinositide hydrolysis or the levels of the parent lipids within the membrane. Forskolin induced a much larger stimulation of cyclic AMP than did serotonin, and caused an increase in the levels of phosphatidylinositol-4-phosphate and phosphatidyl inositol-4,5-bisphosphate in the cell membrane.
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PMID:Activation of dopamine receptors does not affect phosphoinositide turnover in NCB-20 cells. 303 93

The GTP binding regulatory protein (Ni involved in adenylate cyclase inhibition was purified from rat brain and reconstituted, together with muscarinic cholinergic receptors purified from porcine brain, into phospholipid vesicles. Guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding and GTP hydrolyzing activities of reconstituted Ni were stimulated by the addition of a muscarinic agonist, carbachol. The effect of carbachol was to increase the Vmax values of these activities, but the Km values were also increased slightly in most cases. Carbachol bound to vesicles with the same order of magnitude of Km as that for stimulation of GTPase. The affinity of this binding was reduced by GTP gamma S, indicating that the high-affinity receptor-Ni complex was formed in a GTP-dependent manner in reconstituted vesicles. Incubation of Ni with NAD and islet-activating protein (IAP), pertussis toxin, caused ADP-ribosylation of the alpha-subunit of Ni. The criteria for the receptor-Ni interaction, i.e. carbachol stimulation of the activities of Ni and the GTP gamma S effect on carbachol binding, were no longer observed, when this IAP-treated Ni, instead of the nontreated Ni, was reconstituted into vesicles, though there was no difference between IAP-treated and nontreated Ni in their basal activities observable without carbachol. No, the protein with a character very similar to Ni in rat brain, was also coupled to muscarinic receptors when they were reconstituted into vesicles under the same conditions. Thus, GTP-binding proteins serving as the substrate of IAP-catalyzed ADP-ribosylation are capable of interaction functionally with muscarinic receptors in phospholipid vesicles.
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PMID:Functional interaction of purified muscarinic receptors with purified inhibitory guanine nucleotide regulatory proteins reconstituted in phospholipid vesicles. 308 83

Muscarinic cholinergic agonists have been shown to inhibit PRL secretion in normal and tumor-derived pituitary cells. Evidence from experiments with the fluorescent Ca2+ probe quin 2 shows that carbachol, acting through muscarinic acetylcholine receptors, lowers the cytosolic free Ca2+ concentration ([Ca2+]i), in GH3 cells. A decrease in [Ca2+]i is observed rapidly after carbachol addition, the lowered steady state [Ca2+]i is maintained, and upon the addition of atropine [Ca2+]i returns to the initial basal value. The lowering from a basal [Ca2+]i, averaging 110 +/- 2 nM (+/- SEM, n = 9), to a steady state [Ca2+]i of 63 +/- 4 nM (+/- SEM, n = 5) at 10 micron carbachol is dose dependent, a significant decrease from basal [Ca2+]i being observed at 0.1 micron. Carbachol does not prevent TRH-induced mobilization of Ca2+ but attenuates the resulting rise in [Ca2+]i. The lowering of steady state [Ca2+]i and the attenuation of the rise in [Ca2+]i provoked by stimulators of PRL secretion could explain the inhibition of both basal and stimulated PRL secretion. Concomitantly with the action on [Ca2+]i, carbachol causes hyperpolarization of GH3 cells. Together with the established inhibition of adenylate cyclase by muscarinic cholinergic agonists, these findings suggest a relation between changes in trans-membrane Ca2+ fluxes and cAMP generation.
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PMID:Lowering of cytosolic free Ca2+ by carbachol, a muscarinic cholinergic agonist, in clonal pituitary cells (GH3 cells). 392 73

The interaction of two coexisting transmitters in the cat submandibular gland has been elucidated by studying effects of VIP and carbachol on cyclic AMP accumulation in isolated acini from the gland. Carbachol was found to potentiate the cyclic AMP increase induced by VIP by an atropine sensitive mechanism. The effect of carbachol on cyclic AMP accumulation was abolished by including EGTA in the incubation medium as was the carbachol mediated potentiation of VIP responses. The calmodulin inhibitor trifluoperazine had a similar, but less marked effect. The effect of carbachol was mimicked by phenylephrine (30 microM) and by the calcium inophore A 23187 (3 microM), and also by ethanol in a concentration reported to enhance membrane fluidity. The phospholipase A2 inhibitor, mepacrine, tended to decrease carbachol actions. Our results show that the potentiation of VIP responses in feline submandibular gland is calcium-dependent. The mechanism could involve a calcium-calmodulin-induced stimulation of adenylate cyclase or calcium-induced change in membrane phospholipid metabolism.
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PMID:Calcium-dependent enhancement by carbachol of the VIP-induced cyclic AMP accumulation in cat submandibular gland. 609 14

The ability of the muscarinic agonist, carbachol, to overcome increases in tension and in cAMP produced in response to the adenylate cyclase activator, forskolin, in rabbit papillary muscles was measured. Forskolin alone increased cAMP levels to a much greater extent than did a concentration of isoproterenol that produced an equivalent increase in tension. Carbachol completely overcame the increase in tension, while having no effect on the increase in cAMP, produced by forskolin. The response to carbachol was associated with a significant increase in cGMP levels. It appears that carbachol may block the inotropic response to forskolin by antagonizing the effects of forskolin-induced increases in cAMP.
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PMID:The interaction of carbachol and forskolin in rabbit papillary muscles. 609 84


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