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)

Drugs thought to increase intracellular levels of cAMP were infused intrathecally into the subarachnoid space of the lumbar spinal cord, and the effects on the acoustic startle response in rats were measured. Intrathecal infusions of the cAMP analogs dibutyryl cAMP or 8-bromo cAMP (12.5-100 micrograms) produced marked, dose-dependent increases in startle amplitude compared to the infusion of artificial cerebrospinal fluid (CSF). Local infusions of dibutyryl cAMP at more rostral levels of the spinal cord or brain failed to mimic the excitatory effect seen following lumbar intrathecal infusion. No excitation of startle was seen following intrathecal infusion of cAMP itself, ATP, 5'-AMP, or dibutyryl cGMP. A weak excitation of startle was seen following intrathecal, but not intraventricular, infusion of the water-soluble adenylate cyclase activator forskolin 7-deacetyl-7-O-hemisuccinic acid (forskolin-DHA; 5.0-100 micrograms, in artificial CSF), whereas forskolin itself [0.01-200 micrograms, in dimethyl sulfoxide (DMSO)] was without consistent effect. Finally, intrathecal infusion of the selective phosphodiesterase inhibitor Rolipram (12.5-200 micrograms) produced a marked excitation of startle similar in magnitude to the effects produced by cAMP analogs. The excitatory effects of intrathecally infused dibutyryl cAMP, 8-bromo cAMP, forskolin-DHA, or Rolipram support a functional link between spinal cord cAMP and the acoustic startle reflex. Possible sites of cAMP action on startle are discussed.
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PMID:The role of spinal cord cyclic AMP in the acoustic startle response in rats. 302 26

beta-Adrenergic receptors in guinea-pig liver plasma membranes were characterized by radioligand binding, using l-[3H]dihydroalprenolol ([3H]DHA), l-3-[125I]iodocyanopindolol ([125I]CYP) and dl-[3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2- one hydrochloride [( 3H]CGP-12177). The binding of both [125I]CYP and [3H]CGP-12177 to membranes exhibited high affinity (Kd = 3.5 +/- 0.2 pM for [125I]CYP and 0.75 +/- 0.10 nM for [3H]CGP-12177) and stereospecificity; the maximal binding sites were 130 +/- 15 and 137 +/- 8 fmoles/mg protein respectively. Catecholaminergic agonists competed for these binding sites in the order l-isoproterenol greater than l-epinephrine greater than l-norepinephrine, which is typical for beta 2-adrenergic receptors. The binding data are supported by parallel experiments on adenylate cyclase activation by catecholamines, and on antagonism of this activation by beta 1- and beta 2-selective blockers. The binding of [3H]DHA was excessive (Bmax = 21.4 pmoles/mg protein), exhibited low affinity (Kd = 34.6 nM), and lacked stereospecificity. When liver membranes were incubated at 50 degrees for 40 min in the presence of an agonist, l-isoproterenol, the binding of [3H]DHA to the heat-treated membranes exhibited high affinity (Kd = 1.07 +/- 0.17 nM) and the Bmax was reduced to 139 +/- 22 fmoles/mg protein. In such membranes, as opposed to native membranes, stereospecificity was evident and catecholaminergic agonists competed for the binding sites in the order typical for beta 2-adrenergic receptors. However, agonist competition of the binding to the heat-treated membranes could not be modulated by guanine nucleotides, indicating a loss of communication between the receptor and the guanine nucleotide regulatory protein.
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PMID:Beta-adrenergic receptors in guinea-pig liver plasma membranes and thermal lability of [3H]dihydroalprenolol binding sites. 302 48

Three groups of male, weanling, Sprague-Dawley rats were fed diets containing 7% hydrogenated coconut oil, 6.6% hydrogenated coconut oil + 0.4% corn oil, or 7% corn oil for 8-17 weeks. These diets provided 0% (EFAD group), 0.5% (MEFAD group) or 5% (CONTROL group) of the total energy as linoleic acid, respectively. Crude plasma membranes were prepared from heart and assayed for adenylate cyclase activity. Both basal and fluoride-stimulated activity was lower in the membranes from EFAD and MEFAD rats than that of the controls. The double bond index of total lipids and phospholipids, and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) were not appreciably different in the membranes from the three dietary groups. The fatty acid composition of total phospholipids of the membranes, however, was quite different and indicative of biochemical changes typical of an EFA deficiency. Feeding of the control diet to the EFAD or MEFAD rats for up to 6 weeks did not alleviate completely the changes in adenylate cyclase activity although the fatty acid patterns were restored to the normal levels. There was also a decrease in the number of [3H]-DHA binding sites in heart of EFAD rats as compared with their controls. The results suggest that the changes induced by EFA deficiency in the acyl group composition of membrane phospholipids and in the number of beta-adrenergic receptors may be important in regulating adenylate cyclase activity in the heart.
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PMID:Adenylate cyclase activity, membrane fluidity and fatty acid composition of rat heart in essential fatty acid deficiency. 362 82

The effect of thyroid hormone on the beta-adrenergic receptor in foetal cardiac membranes was analysed by measuring the binding of (-)[3H]DHA. The specific activities (per mg protein) of beta-adrenergic receptors decreased with advancing gestational age, whereas the total activities (per heart) increased under the similar conditions. The change in the binding affinities was not statistically significant. 1; 3,5,3'-L-triiodothyronine (T3) stimulated the (-)[3H]DHA binding capacities of the cardiac membranes of foetuses of all age groups. The enhancement in the receptor activity was completely inhibited actinomycin D or cycloheximide. The contents of epinephrine, norepinephrine and cAMP increased with advancing gestational age; but T3 had no significant effect on the catecholamines or cAMP. Similarly, the activities of the basal, NaF stimulated and Gpp(NH)p stimulated adenylate cyclase remained unaltered by T3, but the activities increased progressively with foetal maturity. The absolute values of catecholamine stimulated adenylate cyclase activities in the hearts of T3 treated foetuses were, however, higher compared to those in the untreated foetuses. The enhancement of the activities were totally blocked by the action of actinomycin D, cycloheximide or propranolol. Our results indicate that thyroid hormone enhances the number of beta-adrenergic receptor binding sites by synthesizing new receptor proteins resulting in increased catecholamine sensitivity.
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PMID:Thyroid hormone regulation of beta-adrenergic receptors and catecholamine sensitive adenylate cyclase in foetal heart. 608 83

To establish a model of airway smooth muscle function we studied binding of [3H]dihydroalprenolol [( 3H]DHA), a beta-adrenergic antagonist, to membrane preparations of porcine trachealis muscle and investigated the response of adenylate cyclase to l-isoproterenol in tissue and plasma membranes. [3H]DHA binding was of high affinity (Kd = 1.0 +/- 0.1 nM), was saturable (Bmax = 87.6 +/- 13.2 fmol/mg protein), and was 90% beta 2 and 10% beta 1. Adenylate cyclase activity in the membrane preparation was (in pmol.10 min-1.mg protein-1 +/- SE): basal 420 +/- 74, guanosine 5'-triphosphate (GTP) (10 micron) 600 +/- 45, GTP (10 microM) + l-isoproterenol (100 microM) 660 +/- 63, NaF (10 mM) 1,500 +/- 134, and forskolin (100 microM) 3,000 +/- 410. Guanosine 5'-diphosphate (GDP) and GTP were active cofactors; l-isoproterenol appeared to function as an effector exchanging GTP for GDP on the guanine nucleotide regulatory protein. There was close agreement of the effective dose (ED50) of the l-isoproterenol-induced relaxation (0.95 +/- 0.45 microM) and the inhibitory constant of l-isoproterenol binding (0.39 +/- 0.10 microM). l-Isoproterenol (100 microM) induced a 100% increase in adenosine 3',5'-cyclic monophosphate (cAMP) levels in tissue strips over basal activity. Investigation of the difference in adenylate cyclase activity between tissue and plasma membranes revealed that l-isoproterenol responsive adenylate cyclase was diminished after initial homogenization. Electron microscopy demonstrated disruption of all cells at this early stage of preparation. The decrease in l-isoproterenol responsive adenylate cyclase following cell rupture is different from other tissues and suggests a difference in the actions of beta-agonist in smooth muscle compared with other tissues.
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PMID:Characterization of a beta-adrenergic receptor in porcine trachealis muscle. 609 67

C6 glioma cells possess beta adrenergic receptors coupled with adenylate cyclase which can be irreversibly blocked by bromoacetylaminomethylpindolol (Br-AAM-pindolol), a beta adrenergic antagonist. With 1 microM Br-AAM-pindolol, more than 80% of beta adrenergic receptors, labeled by (3H)-dihydroalprenolol [3H)-DHA), were blocked. After this blockade, new beta adrenergic receptors were synthesized only during cell division. However, at cell confluency when the cell number was constant, turnover of beta adrenergic receptors was barely detectable. Cycloheximide (1 microgram/ml) inhibited cell growth as well as reappearance of beta adrenergic receptors. A 90% loss of beta adrenergic receptors in C6 glioma cells was obtained after down-regulation for 15 h with 10 microM isoproterenol, a beta adrenergic agonist. After removal of the agonist, recovery of beta-adrenergic-sensitive adenylate cyclase was complete within 2 to 3 days, whereas beta adrenergic receptors reached 90% of control value within 6 days. The half-life of the receptor recovery was 2 to 3 days. Pretreatment of C6 glioma cells by Br-AAM-pindolol and subsequent cell exposure to isoproterenol indicated that down regulation and recovery of unblocked beta adrenergic receptors did occur; however isoproterenol did not accelerate the biosynthesis of beta adrenergic receptors. The recovery of both biological response and beta adrenergic receptor occupancy was restored both in the presence or absence of cycloheximide (1 microgram/ml), a concentration which blocked 90% of protein synthesis. Our results suggest that reappearance of beta adrenergic receptors in C6 glioma cells, following isoproterenol-induced down regulation, was not due to synthesis of new receptors but to recycling of the beta adrenergic receptors.
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PMID:Beta adrenergic receptor repopulation of C6 glioma cells after irreversible blockade and down regulation. 609

The prolonged in vitro perfusion of rat lung with isoproterenol (Iso) induced a desensitization of beta-adrenoceptors which was dose- and time-dependent. The decrease in functional responsiveness of rat lung parenchyma to the beta-agonist correlated well with the loss of [3H]dihydroalprenolol ([3H]DHA) binding sites and adenylate cyclase activity after the beta-adrenoceptor desensitization procedure. The cyclooxygenase inhibitor indomethacin prevented the beta-adrenoceptor desensitization as was shown by the restored isoproterenol-induced relaxation in rat lung parenchyma strips and adenylate cyclase activity after the milder desensitization procedure. Inhibition of the arachidonic acid cascade at different levels with different compounds such as BW 755C and betamethasone prevented the desensitization of beta-adrenoceptors. These findings suggest a role for arachidonic acid metabolites in beta-adrenoceptor desensitization. The possible sites of action of arachidonic acid metabolites are also discussed in relation to the inability of indomethacin to prevent the desensitization of beta-adrenoceptors that was induced by the higher Iso concentration used.
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PMID:Involvement of arachidonic acid metabolites in beta-adrenoceptor desensitization: functional and biochemical studies. 609 63

Rat serosal mast cell beta-adrenergic receptors were characterized both functionally by assessing changes in histamine release and cyclic 3',5' adenosine monophosphate (cAMP) levels and directly by radioligand binding studies using [3H]dihydroalprenolol ([3H]DHA), a beta-adrenergic antagonist. Mast cells were obtained by lavage of the pleural and peritoneal cavities of Sprague-Dawley rats and were purified on metrizamide gradients to greater than 95% purity. Resting mast cells stimulated with beta-adrenergic agonists demonstrate a marked rise in cAMP levels after a 15-sec incubation. However, the same concentrations of these agonists have no effect on IgE-mediated mast cell histamine release. [3H]DHA binding to intact mast cells is rapid, reversible, saturable, and stereoselective. The cells possess 40,000 +/- 14,000 beta-adrenergic receptors/cell and demonstrate a binding affinity of 1.58 +/- 0.56 nM for [3H]DHA. Competition studies reveal that 83.5% of the receptors are of the beta 2 subtype and 16.5% are beta 1. Neither sensitization with anti-DNP-BSA IgE nor subsequent challenge with specific antigen alters mast cell beta-adrenergic receptor characteristics. Rat mast cells possesses large numbers of high affinity beta-adrenergic receptors, primarily of the beta 2 subtype, coupled to adenylate cyclase, but the role of these receptors in mast cell secretory events is not yet established.
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PMID:Characterization of the rat mast cell beta-adrenergic receptor in resting and stimulated cells by radioligand binding. 612 1

The effect of sulfhydryl compounds on binding of the beta-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA] to a microsomal fraction from rabbit skeletal muscle was examined. Inhibition of binding by a variety of adrenergic agonists and antagonists and the effects of these agents on adenylate cyclase were consistent with the beta-adrenergic receptor in this tissue being of the beta 2-subtype. Binding of (-)-[3H]DHA was reduced by incubating the membranes with dithiols such as dithiothreitol (DTT), 1,3-dimercapto-2-propanol and 1,4-dimercaptobutane; monothiols were much less potent. DTT-induced decline in (-)-[3H]DHA binding resulted primarily from a decrease in receptor number. Inactivation was partially reversed by the oxidant H2O2. Binding sites could be locked in the inactivated state by incubating DTT-treated membranes with the alkylating agent iodoacetamide. Both beta-adrenergic agonists and antagonists protected against inactivation. Adenylate cyclase activity in the membranes was increased by DTT. The enzyme was rapidly inactivated by H2O2, and this could be partially reversed by DTT. It is concluded that the beta-adrenergic receptor of skeletal muscle contains an essential disulfide moiety which can be inactivated by reducing dithiols. Adenylate cyclase, on the other hand, contains at least one essential sulfhydryl which is preserved by dithiols.
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PMID:Inactivation of the beta-adrenergic receptor in skeletal muscle by dithiols. 613 19

beta-Adrenoreceptor antagonists containing several pharmacophores, so called alprenolol-Jeffamines, were studied. These compounds are derived from Jeffamine NH2-CH-(CH3)-CH2-[-O-CH2-CH(CH3)-]n-NH2, n = 2.6 ave. by substitution of nitrogen with 3-(2-allylphenoxy)-2-hydroxypropyl groups, which are part of the Alprenolol pharmacophore. Alprenolol-Jeffamines inhibited (-)isoprenaline stimulated adenylate cyclase activity; the derivative with one pharmacophore was about 4-fold and the derivative with two pharmacophores was about 17-fold less potent than (+/-)alprenolol; the trisubstituted derivative which has one complete and two partial pharmacophores was ineffective. The ratio of Ki's for inhibition of (-)3H-DHA binding and for inhibition of adenylate cyclase were approximately one for each derivative. When (+/-)alprenolol and alprenolol-Jeffamine derivatives were injected intraperitoneally into rats and heart membranes or homogenates were prepared 18-20 h afterwards, the mono, di, and trisubstituted derivatives, but not (+/-)alprenolol, inhibited binding of (-)3H-DHA. This persistency pattern is different from that observed in vitro, where only di and trisubstituted derivatives are persistent. Slow metabolism/slow excretion of the monosubstituted derivative may be a source of the increased persistency in vivo. In similarly prepared animals, the dose-response curve for (-)isoprenaline stimulated adenylate cyclase was shifted to the right 3-to-4 fold for mono and disubstituted derivatives but was unaffected by (+/-)alprenolol and the trisubstituted derivative. The results suggest that these derivatives interact with physiologically important beta-adrenoreceptors in vitro, and that, in vivo, they persistently block beta-adrenoreceptors and inhibit isoprenaline stimulated adenylate cyclase.
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PMID:Beta-adrenoreceptor antagonists with multiple pharmacophores: persistent inhibition of rat heart adenylate cyclase. 613 83


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