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 total muscarinic (M1 + M2 + M3) and beta-adrenergic receptors in the tracheal smooth muscle of conventional and double-muscled calves were identified and characterized with the non-specific antagonists [3H]quinuclidinyl benzilate ([3H]QNB) and [3H]dihydroalprenolol ([3H]DHA) respectively. Although the quantity of beta-adrenoceptors in double-muscled calves was 25% lower (p < 0.05) than in conventional calves (Bmax = 327 +/- 89 fmol/mg protein), adenylate cyclase assays indicated that the basal adenylate cyclase activity and the (-)-isopropylnoradrenaline (ISO)- and sodium fluoride (NaF)-stimulated values were not significantly different between these calves. However, the density of muscarinic receptors in double-muscled calves was 40% higher (p < 0.01) than in conventional calves (Bmax = 2955 +/- 625 fmol/mg protein). Subtypes of muscarinic receptors were studied with [3H]telenzepine (M1-receptors), [3H]AF-DX 384 (M2-receptors) and [3H]4DAMP (M1 and M3-receptors). It was found that in both double-muscled and conventional calves about 40% of the receptors were of the M3-subtype, the remaining 60% being M2-receptors. From these results, it is suggested that inflammation of the respiratory tract in double-muscled calves may be complicated by an imbalance between the cholinergic bronchoconstrictor and the beta-adrenergic bronchodilator components of the autonomic nervous system.
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PMID:Muscarinic receptor subtypes, beta-adrenoceptors and cAMP in the tracheal smooth muscle of conventional and double-muscled calves. 133 39

Since acetylcholine (ACh) was identified as a neurotransmitter at parasympathetic nerve terminals by pioneering pharmacologists such as O. Schmiedeberg, R. Hunt, O. Loewi and H.H. Dale, muscarinic acetylcholine receptors (mACh-R) serving as a transducer of muscarinic action have been assumed to exist. After many tries to identify the mACh-R, it's existence was established by the group of S.H. Snyder, who employed binding assays with the radioligand 3H-QNB. The presence of a neuronal (M1) and a peripheral (M2) mACh-R was suggested from the action of an M1-specific agonist, McN-A-343; and this observation was followed by the discovery that the antagonist pirenzepine had higher affinity for M1 than for M2. Later, peripheral mACh-Rs were further subclassified in two types by the heart-specific action of gallamine and the different affinities of AF-DX116 and 4-DAMP. At present, three subtypes, M1 (neuronal), M2 (heart) and M3 (other peripheral organs), can be pharmacologically distinguished by affinity differences. On the other hand, purification of mACh-R and analysis by gene technology revealed the presence of five mACh-R mRNAs (m1-m5), which were expressed in various organs with different abundances. These subtypes couple with subcellular muscarinic responses through different GTP-binding proteins. The connection between the subtypes, GTP-binding proteins and responses is not fully understood yet. Our studies showed that in guinea pig heart, in which only m2 mRNA is expressed, muscarinic agonists recognize two subgroups (M2 alpha and M2 beta) with different affinities. One couples with the inhibition of adenylate cyclase, and the other couples with PI turnover through different GTP-binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Progress in the study of muscarinic acetylcholine receptors; establishment of the subtypes or subgroups]. 210 3

The biochemical linking event between the activation of muscarinic receptors and the inhibition of adenylate cyclase was studied with rat heart ventrical membranes. The muscarinic M2 selective antagonists were more potent than the M1 selective antagonists in the displacement of non-selective labeled 3H-QNB binding to the membranes. This was also true for the M2 selective agonists, with respect to the M1 selective agonists, in the reaction medium without Gpp(NH)p. With the same preparation, the muscarinic M2 selective agents were also more potent than the M1 selective agents in the inhibition of adenylate cyclase activity. The order of potencies of these agents in the displacement of 3H-QNB binding correlated well with their order of potencies in inhibiting adenylate cyclase activity. Gpp(NH)p reduced the binding affinities of M2 selective agonists (i.e. carbachol and oxotremorine), while it did not affect the binding affinities of non-selective agonist pilocarpine, M1 selective agonist McN-A-343 and antagonists (i.e. pirenzepine, trihexyphenidyl, AF-DX-116 and methoctramine). These results suggest that in the rat heart, the inhibition of adenylate cyclase by muscarinic agonists is through activation of the M2 subtype receptor and G-protein is likely to be involved in the coupling.
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PMID:Muscarinic M2 receptors coupled to inhibition of adenylate cyclase in rat heart. 212 26

Unilateral stereotaxic injection of small amounts of the cholinotoxin, AF64A, caused minimal nonselective tissue damage and resulted in a significant loss of the presynaptic cholinergic markers [3H]hemicholinium-3 (45% reduction) and choline acetyltransferase (27% reduction). No significant change from control was observed in tyrosine hydroxylase or tryptophan hydroxylase activity; presynaptic neuronal markers for dopamine- and serotonin-containing neurons, respectively. The AF64A lesion resulted in a significant reduction of dopamine D2 receptors as evidenced by a decrease in [3H]sulpiride binding (42% reduction) and decrease of muscarinic non-M1 receptors as shown by a reduction in [3H]QNB binding in the presence of 100 nM pirenzepine (36% reduction). Saturation studies revealed that the change in [3H]sulpiride and [3H]QNB binding was due to a change in Bmax not Kd. Intrastriatal injection of AF64A failed to alter dopamine D1 or muscarinic M1 receptors labeled with [3H]SCH23390 and [3H]pirenzepine, respectively. In addition, no change in [3H]forskolin-labeled adenylate cyclase was observed. These results demonstrate that a subpopulation of muscarinic receptors (non-M1) are presynaptic on cholinergic interneurons (hence, autoreceptors), and a subpopulation of dopamine D2 receptors are postsynaptic on cholinergic interneurons. Furthermore, dopamine D1, muscarinic M1 and [3H]forskolin-labeled adenylate cyclase are not localized to striatal cholinergic interneurons.
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PMID:Muscarinic and dopaminergic receptor subtypes on striatal cholinergic interneurons. 214 67

The effects of the neurotoxin aluminum on markers of synaptic neurotransmission, adenosine 3',5'-monophosphate, and neurofilaments have been evaluated in a neuroblastoma x glioma hybridoma (NG108-15). Cells were exposed for 4 days to 2 mM aluminum lactate, a concentration that did not suppress growth. Compared to controls, the activity of choline acetyltransferase was significantly increased by 37% associated with an up-regulation in enzyme activity (Vmax). Muscarinic receptors, measured by [3H]QNB binding, were reduced by 41%. In contrast, the activities of acetylcholinesterase and glutamate decarboxylase were not significantly changed. Aluminum raised the level of cyclic AMP by 20%, although adenylate cyclase activity was unchanged. Small amounts of both phosphorylated and non-phosphorylated neurofilaments were detected in NG108-15 cells. Aluminum intoxication, however, did not alter the quantity, ultrastructure, or immunoreactivity of neurofilaments. Our results demonstrate the capability of aluminum to produce selected changes in cholinergic markers and levels of cyclic AMP in a rapidly dividing cell line.
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PMID:The effect of aluminum on markers for synaptic neurotransmission, cyclic AMP, and neurofilaments in a neuroblastoma x glioma hybridoma (NG108-15). 217 66

In the present work we characterized both the presynaptic and postsynaptic components of cholinergic transmission in a primary culture of corticostriatal neurons prepared from newborn rat brain. This culture preparation contains a small population of choline acetyltransferase (ChAT) immunoreactive neurons, corresponding to approximately 3% of the total cell number, and synthesizes increasing amounts of acetylcholine (ACh) from the third day in vitro (DIV), which reaches a plateau around the 10 day of culture. Muscarinic cholinergic receptors (mAChR), measured by the binding of the muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB), are detectable from the fifth DIV and increase linearly during the time of culture. At the twelfth DIV, the density of mAChRs (approximately 600 fmol/mg protein) is comparable to the density of mAChR in adult rat cortex. These receptors are coupled to second messenger systems, since muscarinic agonists inhibit adenylate cyclase activity and stimulate phosphoinositide breakdown with efficacies and potencies similar to those found in adult rat cortex. Moreover, by using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique, we were able to demonstrate the presence of the m1, m3, and m4 mAChR subtype mRNAs in this neuronal culture at 12 DIV. Our data suggest that corticostriatal neuronal cultures develop in vitro ACh-synthesizing neurons and functionally active cholinergic receptors. This therefore makes them ideally suited to study the development and properties of brain mAChR subtypes.
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PMID:Primary cultures of corticostriatal cells from newborn rats: a model to study muscarinic receptor subtypes regulation and function. 217 49

In primary cultures of cerebellar granule cells, activation of muscarinic receptors stimulates both hydrolysis of phosphatidylinositol (PI) and inhibition of adenylate cyclase. The specificity of three muscarinic receptor antagonists, pirenzepine, methoctramine and (-)quinuclidinyl xanthene-9-carboxylate [(-)QNX], in blocking carbachol-stimulated hydrolysis of PI and inhibition of adenylate cyclase were determined. Pirenzepine was found to be nonspecific in blocking the carbachol-stimulated hydrolysis of PI and inhibition of adenylate cyclase, while methoctramine specifically antagonized carbachol-stimulated inhibition of adenylate cyclase with 600 times greater potency than carbachol-stimulated hydrolysis of PI. (-)Quinuclidinyl xanthene-9-carboxylate was approximately 20 times more potent in blocking the carbachol-stimulated hydrolysis of PI than inhibition of adenylate cyclase. Studies of the ability of these three antagonists to block the binding of [3H]quinuclidinyl benzilate [( 3H]QNB) to muscarinic sites on membranes from cerebellar granule cells, revealed that all three antagonists displayed binding characteristics, characteristic of two binding sites, possibly representing the two types of muscarinic receptors. However, the ratio of the affinities for each of the two binding sites was about ten for pirenzepine, 100 for methoctramine and 650 for (-)QNX. Thus, the specificity of these antagonists, in blocking the inhibition of adenylate cyclase and hydrolysis of PI did not correlate with their specificities obtained with the binding studies with [3H]QNB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specificity of methoctramine in blocking muscarinic receptors which inhibit adenylate cyclase in cerebellar granule cells. 229 64

In previous studies, we showed that cardiac muscarinic receptors (M2) are composed of two subgroups, M2 alpha and M2 beta, with different affinities for agonists and that the M2 alpha subgroup is coupled with inhibition of adenylate cyclase. We now studied which subgroup was responsible for the formation of inositol mono- (IP), bis- (IP2), tris- (IP3) and tetrakis- (IP4) phosphates in guinea pig heart. Carbachol (1 mM) significantly stimulated the formation of all four IPs in [3H]myoinositol-preloaded slices of guinea-pig ventricles. Acetylcholine (1 mM) also stimulated the formation of IP2, IP3 and IP4. However, oxotremorine (1 mM) only slightly stimulated the formation of IP2, and pilocarpine did not stimulate the formation of any IP. The pED50 values of carbachol for IP2 and IP3 formation were 3.76 and 4.23, respectively, which coincided with the pKd values of the low-affinity agonist binding site (L site) measured by competition of carbachol with [3H]quinuclidinyl benzilate [( 3H]QNB) binding while the pKd value for inhibition of adenylate cyclase coincided with the pKd value of the high-affinity agonist binding site (H site). Treatment of animals with pertussis toxin decreased the formation of IP2 and IP3 by carbachol to 66 and 54%, respectively, but resulted in complete inhibition of adenylate cyclase. These results suggested that muscarinic stimulation of the formation of IPs was manifested through a different receptor subgroup (M2 beta) and GTP binding protein different from those for inhibition of adenylate cyclase.
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PMID:The H-L subgroup of guinea-pig cardiac M2 receptors (M2 beta) regulates inositol phosphate formation. 258 43

Interaction of the antiarrhythmics moracizine (moricizine, ethmozine, ETHM) and ethacizine (ETHA), the ethyl ester hydrochlorides of 10-(3-R-propionyl)-phenothiazine-2-carbamic acid (where R is morpholine or diethylamine, respectively), with muscarinic cholinergic alpha- and beta-adrenergic systems and histamine H1 receptors (H1-R) has been studied. ETHA and ETHM displaced [3H]-quinuclidinyl benzilate ([3H]-QNB) from muscarinic receptors of M2 type (M2-R) of rabbit heart with Ki = 0.65 +/- 0.07 and 21 +/- 1 mumol/l in atria, 0.77 +/- 0.06 and 22 +/- 3 mumol/l in ventricles; [3H]-pirenzepine ([3H]-PZ) from M1-R of rabbit brain cortex with Ki = 0.70 +/- 0.04 and 3.1 +/- 0.1 mumol/l, respectively. However, only ETHA inhibited the effect of carbachol on rabbit heart adenylate cyclase (AC). ETHM and ETHA bound to alpha 1- and alpha 2-adrenergic receptors (AR) and H1-R of rabbit brain cortex with an affinity in the range of 7-50 mumol/l. Both drugs did not influence epinephrine-sensitive AC of human platelets in concentrations up to 100 mumol/l. They neither bound to beta 1-AR of rabbit heart and beta 2-AR of rat reticulocytes, nor influenced the regulation of AC by isoprenaline (isoproterenol) in the same membrane preparations in concentrations up to 100 mumol/l. The present data shows that ETHA and ETHM in therapeutic doses may have M-cholinolytic properties, ETHA being more potent than ETHM. Coupled with the results of other investigators it might explain the wider spectrum of clinical effects of ETHA as compared with ETHM.
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PMID:Moracizine and ethacizine effects on membrane receptors. 267 52

Experiments were undertaken to determine whether the anticholinergic actions of tricyclic antidepressants are mediated by a selective interaction with a subclass of muscarinic receptors. To this end, the potencies of these antidepressants to inhibit [3H]-QNB binding to rat brain cerebral cortical membranes was compared to their potencies as antagonists of carbachol-stimulated inositol phosphate accumulation in cerebral cortical slices and carbachol-induced inhibition of GTP-stimulated adenylate cyclase in striatal membranes. Whereas amitriptyline was more potent than pirenzepine, a selective muscarinic M1 receptor antagonist, in competing for [3H]-QNB binding sites and as an antagonist of carbachol-induced inhibition of adenylate cyclase, pirenzepine was substantially more active (ten-fold) than amitriptyline in blocking carbachol-stimulated phosphatidyl inositol turnover. Atropine was more potent than all other agents in these assays, failing to display any significant degree of selectivity. The results suggest that the tricyclic antidepressants, in particular amitriptyline, appear to be selective antagonists for muscarinic receptors associated with adenylate cyclase in striatal membranes. Given the current classification of cholinergic receptors, these findings indicate that the tricyclic antidepressants may be useful for defining the properties of M2 receptors in brain.
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PMID:Selective interaction of tricyclic antidepressants with a subclass of rat brain cholinergic muscarinic receptors. 303 13


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