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)

Ventricular and atrial myocytes cultured from chick embryos 14 days in ovo were used as model systems to study cardiac adenosine receptors. In membranes of ventricular cultures, blocking of the A1-adenosine receptor pathway by the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or by pertussis toxin treatment of the myocyte resulted in a significant adenosine agonist-mediated stimulation of the adenylate cyclase activity. The maximal increases in adenylate cyclase activity caused by the equipotent or the A2-adenosine receptor-selective agonists (from 52.1 +/- 3% to 63 +/- 10% [mean +/- SEM]) were significantly greater than those caused by the A1-selective agonists (from 11 +/- 5% to 34.6 +/- 7%) (p less than 0.01, by t test, n = 4-8). However, in membranes of atrial myocytes, when A1-subtype had been blocked, the various adenosine agonists had no effect on the adenylate cyclase activity. Whether the stimulatory adenylate cyclase-coupled adenosine receptor is also capable of stimulating contractility in the intact ventricular myocyte was next investigated. In ventricular but not in atrial cells, the various adenosine agonists caused an increase in the contractile amplitude in the presence of DPCPX or in myocytes preexposed to pertussis toxin. The increase in contraction amplitude caused by each agonist was expressed as percent of maximum (maximum is the increase in contractility caused by 2.4 mM calcium). In the pertussis toxin-treated myocyte, the maximal increases caused by the equipotent or A2-agonists (NECA, MECA, CV-1808, and CGS21680, from 49.6 +/- 3% to 52.5 +/- 6%, n = 8-12) were significantly greater than those elicited by the A1-agonists (2-CADO, S-PIA, R-PIA, and DCCA, from 12 +/- 4% to 37 +/- 3%, n = 8) (p less than 0.05, by t test). These data demonstrated that a stimulatory adenosine receptor, likely the A2-adenosine receptor, was present on the ventricular but not the atrial myocytes and was linked directly to a stimulation of the cardiac contractility. The functional effects mediated by the A1-subtype became manifested in the presence of isoproterenol, as evidence by an inhibition of the isoproterenol-stimulated increases in adenylate cyclase activity and in cardiac contractility by adenosine agonists. Thus, both subtypes of adenosine receptors, each mediating opposing responses, were present on the ventricular myocytes, whereas only the A1-subtype was found in the atria. The presence of a stimulatory functional A2-adenosine receptor may help explain the absence of a direct negative inotropic response to adenosine in the ventricle.
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PMID:Expression and pharmacological characterization of a stimulatory subtype of adenosine receptor in fetal chick ventricular myocytes. 172 88

In rat olfactory bulb, stimulation of muscarinic receptors activates adenylate cyclase. In the present study we have examined a variety of muscarinic receptor stimulants to characterize the agonist profile of this response. Analysis of agonist concentration-response curves revealed the following rank order of potency: oxotremorine-M greater than oxotremorine greater than BM5 greater than acetylcholine greater than carbachol = methacholine greater than (+/-)muscarine greater than arecoline greater than pilocarpine greater than RS 86 greater than McN-A-343 greater than bethanechol. Acetylcholine, oxotremorine-M, carbachol, (+/-)muscarine and metacholine behaved as full agonists, whereas the other stimulants displayed lower efficacies. The slope values of the concentration-response curves were close or equal to 1, except those of the carbachol and pilocarpine curves, which showed values significantly lower than 1. Moreover, the slope of the pilocarpine curve was differentially changed by the M1 antagonist pirenzepine and the M2 antagonist AF-DX 116. The agonist profile of the muscarinic stimulation of adenylate cyclase in the olfactory bulb correlated well with that exhibited by the muscarinic inhibition of the enzyme activity in the striatum, suggesting that the two responses are mediated by a similar receptor subtype. Sodium ion modulated the agonist affinity for both adenylate cyclase-coupled receptor systems.
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PMID:Muscarinic stimulation of adenylate cyclase activity of rat olfactory bulb. I. Analysis of agonist sensitivity. 194 16

Striatal neurons in primary culture express a wide variety of adenylate cyclase-coupled receptors, and particularly dopamine (DA) D1 receptors, which are known to induce an increase in cyclic AMP production. To study desensitization of those receptor-mediated responses, neurons were incubated in the presence of saturating concentrations of DA for various times. We observed a rapid desensitization of the D1 response after 15 min, which reached a maximum after 18 h. This effect is reversible since incubation of treated neurons in fresh medium led to a complete recovery of the dopamine response within 2 days. In addition, a brief treatment with DA resulted in heterologous desensitization of beta-adrenoceptors and 5-HT and vasoactive intestinal peptide (VIP) receptors coupled to adenylate cyclase on striatal neurons. Similar to what was observed for homologous desensitization, these effects are obtained within the first 15 min of exposure to DA; however, they are short-lasting, even in the persistent presence of DA.
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PMID:Dopamine-induced homologous and heterologous desensitizations of adenylate cyclase-coupled receptors on striatal neurons. 217

Cell-free desensitization of the pigeon erythrocyte adenylate cyclase-coupled beta-adrenoreceptor system requires soluble cellular factors. Desensitization is observed when a mixture of cell membranes and the cytosol fraction are incubated with isoproterenol or cAMP and IBMX for 20 min at 37 degrees C. Mg2+ and ATP are also required for cell-free desensitization. When adenylate cyclase is maximally stimulated by isoproterenol or GTP-gamma-S, the decrement of activity is 45-50% and 20-25%, respectively. Adenylate cyclase desensitization may be also produced by preincubation of plasma membranes with the catalytic component of cAMP-dependent protein kinase. Cell-free desensitization is associated with functional uncoupling of the beta-receptor. This is evidenced by an impaired ability of receptors to form a high affinity, guanine nucleotide-sensitive complex with the agonist and by the increase of the lag-phase of adenylate cyclase activation by isoproterenol and GTP-gamma-S. These findings suggest that one possible mechanism for the development of desensitization in adenylate cyclase systems may be the phosphorylation of a component(s) of the beta-receptor-adenylate cyclase complex which results in impaired receptor-cyclase coupling.
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PMID:Factors essential for desensitization of pigeon erythrocyte adenylate cyclase responsiveness in a cell-free system. 240 78

We have recently shown that both heterologous and homologous forms of adenylate cyclase desensitization involve phosphorylation of beta-adrenergic receptors. In order to compare these two reactions, we wished to identify a single cell system in which both processes could be studied. Using the frog erythrocyte, which has been previously shown to exhibit cAMP-independent homologous desensitization, we have found that under appropriate conditions cAMP-dependent heterologous desensitization can be elicited. Incubation of intact cells with the membrane-permeable cAMP analogs dibutyryl cAMP or 8-bromo cAMP promotes about a 50% desensitization of isoproterenol- and prostaglandin E1-stimulated adenylate cyclase activity in a time-, temperature-, and dose-dependent fashion. There is also a 20% desensitization in the abilities of guanine nucleotides (GTP and guanyl-5'-yl-imidodiphosphate) and NaF to stimulate adenylate cyclase maximally. In contrast, there is no effect on forskolin- or MnCl2-stimulated enzyme activities. The desensitization response is specific for cAMP as dibutyryl cGMP, 8-bromo cGMP, or 8-bromo AMP produce little or no desensitization. Incubation of the cells with dibutyryl cAMP does not affect the number of cell surface beta-adrenergic receptors. In contrast, incubation with isoproterenol promotes homologous desensitization and sequestration of the receptors. Incubation of 32P-labeled erythrocytes with either dibutyryl cAMP or isoproterenol promotes a stoichiometric threefold increase in the phosphorylation state of the beta-adrenergic receptor which occurs predominantly on serine residues. However, if the cells are coincubated with both dibutyryl cAMP and isoproterenol then the desensitization of isoproterenol-stimulated enzyme activity and phosphorylation of the beta-adrenergic receptor are greater than those observed with either agent alone. These results indicate that heterologous and homologous desensitization of adenylate cyclase-coupled beta-adrenergic receptors are mediated by different biochemical pathways involving phosphorylation of the receptor protein on distinct sites.
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PMID:Phosphorylation of the beta-adrenergic receptor in intact cells: relationship to heterologous and homologous mechanisms of adenylate cyclase desensitization. 244 63

Sudden cessation of prolonged treatment with clonidine in conscious rats evokes a cardiovascular withdrawal syndrome, characterized by severe tachycardia and brief blood pressure (BP) increases, so-called "upswings." Previously, adenylate cyclase-coupled alpha 2-adrenoceptors were shown to be involved in this phenomenon. In the present study, the effect on the intensity of clonidine withdrawal symptoms of concomitant treatment with various beta-adrenoceptor antagonists during clonidine infusion (100 micrograms/kg/24 h, 7 days) was investigated. Propranolol (18 mg/kg/24 h, beta 1 and beta 2 blocker) and ICI 118.551 (12 mg/kg/24 h, beta 2 blocker) clearly aggravated the withdrawal symptoms, whereas metoprolol (18 mg/kg/24 h, beta 1 blocker) did not affect the severity of the withdrawal syndrome. Accordingly, intensification of the withdrawal syndrome appears to be mediated by beta 2- rather than by beta 1-adrenoceptors. These results point to an interaction at the level of the second-messenger adenylate cyclase (AC) system in development of clonidine withdrawal syndrome.
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PMID:Beta 2-adrenoceptor antagonists intensify clonidine withdrawal syndrome in conscious rats. 248 78

Histamine induces dose-dependent increases in inositol-monophosphate, inositol-bisphosphate, and inositol-triphosphate in cultured human pulmonary artery and umbilical vein endothelial cells. Preincubation with isoproterenol results in synergistic potentiation of polyphosphoinositide breakdown. Isoproterenol does not change the effect of histamine, however, it does increase the potency of histamine in stimulating phosphoinositide turnover. This effect of isoproterenol is time-dependent reaching 350% at 120 min of preincubation. A synergistic potentiation of histamine-induced polyphosphoinositide breakdown by cyclic AMP stimulators has been observed after pretreatment of cultured endothelial cells with forskolin, dibutyryl cyclic AMP and cholera toxin. Our data suggest that isoproterenol potentiates histamine-induced polyphosphoinositide breakdown by operating via the adenylate cyclase system. This is the first evidence of synergistic potentiation of polyphosphoinositide breakdown by adenylate cyclase-coupled receptors in cultured human endothial cells.
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PMID:Synergistic potentiation of polyphosphoinositide breakdown by adenylate cyclase coupled receptors in human endothelial cells. 254 24

Compound BM5 [N-methyl-N(1-methyl-4-pyrrolidino-2-butynyl) acetamide] has previously been described as an agonist at postsynaptic muscarinic receptors and as an antagonist at presynaptic receptors. In the current work, we studied the ability of this compound to selectively stimulate phosphoinositide (PI) turnover in Chinese hamster ovary cells transfected with m1 muscarinic receptors and in SK-N-SH neuroblastoma cells that express only m3 receptors. We also studied the ability of this compound to stimulate adenylate cyclase inhibition in m2 muscarinic receptors from heart tissue and in m4 receptors expressed in NG108-15 cells. BM5 stimulated the two muscarinic receptor subtypes coupled to adenylate cyclase inhibition. In NG108-15 cells, 100 microM BM5 inhibited prostaglandin E1-stimulated cAMP formation by 36 +/- 1.5%, whereas 100 microM of the full agonist oxotremorine-M inhibited cAMP formation by 64.1 +/- 1.9%. The half-maximal concentration for BM5 inhibition of cAMP formation was 0.4 +/- 0.1 microM. In heart membranes, BM5 inhibited isoproterenol-stimulated adenylate cyclase by 24 +/- 2%, whereas oxotremorine inhibited this activity by 34 +/- 3%. In contrast to its activity at these receptor subtypes, BM5 did not stimulate the m1 or m3 receptor subtypes, which couple to PI turnover. In these latter two subtypes, BM5 inhibited oxotremorine-M-stimulated PI turnover with IC50 values of 10-20 microM. Therefore, BM5 is a partial agonist at adenylate cyclase-coupled muscarinic receptor subtypes and is a pure antagonist at PI turnover-coupled muscarinic receptor subtypes. These studies also suggest that, at least in some parts of the brain, postsynaptic muscarinic receptors are coupled to adenylate cyclase, whereas presynaptic muscarinic receptors are coupled to PI turnover.
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PMID:An agonist that is selective for adenylate cyclase-coupled muscarinic receptors. 255 Jul 80

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.
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PMID:Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor. 256 96

A human beta-adrenergic receptor cDNA was transfected and expressed in transformed Chinese hamster fibroblasts (CHW). The expressed receptor exhibited a typical beta 2-adrenergic selectivity for agonists and antagonists as assessed by radioligand binding and adenylate cyclase activation. Guanine nucleotide-sensitive high affinity binding of the agonist, isoproterenol, indicated effective coupling of the expressed receptor to a guanine nucleotide-regulatory protein. The level of expression of beta 2-AR in various cell clones varied over 200-fold and was positively correlated with the levels of beta 2-AR mRNA. In cells expressing between 0.04 and 3.0 pmol of beta 2-AR/mg of membrane protein, the efficacy of isoproterenol for stimulating adenylate cyclase increased with increasing numbers of expressed receptors but reached a plateau and started to decrease in clones with higher beta 2-AR density (3.0-8.0 pmol/mg of membrane protein). Preincubation of beta 2-AR-expressing cells with isoproterenol for 15 min led to significant reduction in the level of isoproterenol-sensitive adenylate cyclase activity. This agonist-induced desensitization was also accompanied by phosphorylation of the beta 2-AR. These data indicate that the expressed human beta 2-AR displays typical functional characteristics of adenylate cyclase-coupled receptors including agonist-induced desensitization. Moreover, the availability of this series of cellular clones, which differ markedly in their density of beta 2-AR, provides a unique set of biological reagents for future studies of beta 2-AR function and regulation.
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PMID:Expression of a human cDNA encoding the beta 2-adrenergic receptor in Chinese hamster fibroblasts (CHW): functionality and regulation of the expressed receptors. 282 11


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