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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase (TH) a characteristic enzyme activity for the catecholaminergic clonal cell line LA-N-1 and choline acetyltransferase (ChAT) a characteristic enzyme activity for the cholinergic clonal cell line LA-N-2 were previously shown to be increased in these cells exposed to 10(-5) M retinoic acid (RA) as differentiating agent. An investigation of the receptor characteristics suggests a complementarity between the two cell lines. The binding of QNB, a muscarinic ligand, was undetectable with the LA-N-2 cells but was present in the LA-N-1 cells and possessed a kD of 1.8 nM and 2.2 nM and a Bmax of 0.56 and 0.68 for control and RA grown cells respectively. There was a gradual increase in QNB binding to LA-N-1 cells from 2 days in vitro (DIV) until 6 DIV in both control and RA grown cells. An IC50 of 2.5 x 10(-8) M and 0.9 x 10(-8) M for atropine inhibition was obtained for the control and RA grown cells respectively. The corresponding values for carbachol inhibition were 7 x 10(-2) M and 3 x 10(-2) M respectively. The inhibition by the agonist oxotremorine is comparable to that of carbachol and 1 mM pilocarpine inhibited the binding by 21%. QNB binding showed a low affinity for pirenzepine and for AF-DX-116 but was inhibited with a rather high affinity by 4-DAMP (IC50:110 microM) thus suggesting the presence of an M3 receptor. Acetylcholine (100 microM) plus eserine (50 microM) and BW284c55 (1 microM), an acetylcholinesterase inhibitor, reduced the binding of QNB by approximately 25%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic binding sites in a catecholaminergic human neuroblastoma cell line. 132 Feb 13

The effects of muscarinic receptor antagonists on ACh release were studied in the absence or presence of cholinesterase (ChE) inhibition using the isolated perfused chicken heart. Presynaptic inhibitory muscarinic autoreceptor were characterized by determining the potency of various antagonists to enhance [3H]-ACh release evoked by field stimulation (3 Hz, 1 min). The order of potencies was: (+/-)-telenzepine > atropine > 4-DAMP > silahexocyclium > pirenzepine > hexahydro-siladifenid-ol > AF-DX 116. The comparison with known pA2 values for M1-, M2- and M3-receptors revealed that the presynaptic autoreceptor meets the criteria of an M1-receptor. Basal, not electrically evoked overflow of unlabelled ACh into the perfusate was caused by 'leakage' release (non-exocytotic), as it was independent of extracellular Ca2+. Muscarinic receptor antagonists failed to enhance basel overflow. In contrast, when ChE activity was inhibited by 10(-6) M tacrine or pretreatment with 10(-4) M DFP, the ACh overflow was partially Ca(2+)-dependent and was reduced by tetrodotoxine. Moreover, block of the inhibitory muscarinic autoreceptors by (+/-)-telenzepine or pirenzepine caused a several-fold enhancement of the ACh release. The potencies of these antagonists were identical to those found for the electrically evoked [3H]-ACh release. The rate of ACh release enhanced by ChE inhibition plus telenzepine corresponds to about 12% of the total ACh pool per min, which is about the maximum amount of ACh that is available for any kind of stimuli. The release was dependent on the presence of exogenous choline. Hence elevation of ACh release led to a correspondingly enhanced ACh synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibitory and excitatory muscarinic receptors modulating the release of acetylcholine from the postganglionic parasympathetic neuron of the chicken heart. 143 22

1. The muscarinic receptor profile of the sheep ureterovesical junction has been studied by means of in vitro techniques. The relative potency (pD2 = -log EC50) and maximum effect (Emax) observed with carbachol were 51-fold and 25% greater than with acetylcholine respectively. This could be due to the presence of active acetylcholinesterase in this tissue. 2. The pA2 values obtained with the muscarinic antagonists were pirenzepine (8.52), AF-DX 116 (8.05), 4-DAMP (9.41) and hexahydroxiladifenidol (8.66). The slope values of Schild plots were not significantly different from unity, indicating competitive antagonism. Furthermore, when the slopes were constrained to 1, no significant differences were found between the pA2 values. These pA2 values were similar to those observed in other mammalian smooth muscles. 3. It is concluded that muscarinic receptors in the sheep ureterovesical junction smooth muscle belong to the M1, M2 and M3 subtypes and mediate contraction of the ureterovesical junction, which suggests that during parasympathetic stimulation they might prevent vesicoureteral reflux.
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PMID:Mediation of contraction by cholinergic muscarinic receptors in the ureterovesical junction. 162 34

The distribution of cholinergic nerve fibres, as well as the characterization of the muscarinic receptors responsible for the contraction, were determined in the detrusor smooth muscle of the sheep. The results obtained demonstrated a rich presence of acetylcholinesterase (AChE)-positive fibres distributed throughout the bladder body forming dense neuromuscular, subepithelial and perivascular plexuses. Furthermore, intramural ganglia containing AChE-positive cell bodies were identified. However, acetylcholine and carbachol induced a dose-dependent contraction of detrusor smooth muscle. The effect observed with carbachol was competitively antagonized by atropine (pA2: 8.94), pirenzepine (pA2: 7.38), AF-DX 116 (pA2: 7.35), 4-DAMP (pA2: 9.26) and hexahydroxiladifenidol (HHSiD) (pA2: 8.49). The pA2 value for pirenzepine is intermediate between M1- and M2-receptors which suggests that this antagonist does not act on M1- or M2-receptors, but that it does on M3-receptors. The pA2 value for AF-DX 116 is consistent with the presence of M2-receptors in this tissue. Moreover, the pA2 values obtained for both 4-DAMP and HHSiD are in agreement with the presence of M3-receptors, due to the lack of effect of pirenzepine on M1-muscarinic receptors. These results indicate the existence of a rich parasympathetic innervation in the sheep detrusor muscle and suggest that its contraction could be mediated by the stimulation of muscarinic receptors belonging to both M3- and M2-subtypes.
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PMID:Distribution and function of cholinergic receptors in the sheep detrusor muscle. 191 12

Homogenates of calf caudate nuclei were found to contain at least three distinct subclasses of cholinergic, muscarinic receptors. These subtypes, labeled with [3H]quinuclidinyl benzilate (QNB), can be separated by rapid filtration with the use of the selective ligands, pirenzepine, AF-DX116, and 4-DAMP which have high affinity for the M1, M2, and M3 subtypes, respectively. Paraoxon was found to modulate [3H]QNB binding in a noncompetitive manner at concentrations below those needed to affect acetylcholinesterase activity. Pretreatment of the membrane protein with high concentrations of both the M2 selective antagonist, AF-DX116, and the M3 selective antagonist, 4-DAMP, protected against paraoxon inhibition of [3H]QNB binding, while the M1 selective antagonist pirenzepine did not. Paraoxon sensitive sites, M2 and M3, are found predominantly on presynaptic neurons in the central nervous system. It is postulated that blockade of these sites may interfere with negative feedback inhibition of acetylcholine release and facilitate the development of behavioral and motor deficits that may be associated with chronic exposure to low levels of organophosphates.
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PMID:Modulation of central muscarinic receptor binding in vitro by ultralow levels of the organophosphate paraoxon. 279 12

The effects of cholinomimetics and muscarinic antagonists were compared following topical administration to the eyes of anaesthetized rats. For tests with cholinomimetics, clonidine (0.3 mg/kg) was used to induce mydriasis via central inhibition of parasympathetic tone. Full, dose-dependent miosis was induced by acetylcholinesterase inhibitors [physostigmine greater than neostigmine greater than tetrahydroaminoacridine (THA)] and by membrane channel blockers (4-aminopyridine greater than 3,4-diaminopyridine). Oxotremorine was the most potent direct agonist tested [oxotremorine greater than arecaidine propargylester (APE) greater than arecoline greater than carbachol greater than ethoxyethyltrimethyl-ammonium iodide (EOE) greater than RS 86]. Some putative M1 selective agonists were weakly active or behaved as partial agonists (pilocarpine greater than AH6405 greater than Mc-A-343 greater than isoarecoline). Of the antagonists, compared in non-clonidine treated rats, scopolamine hydrochloride was the most potent. Of the receptor selective antagonists the M2 (ileal) selective compounds hexahydrosiladifenidol and 4-DAMP were more potent than either M1 selective (pirenzepine, telenzepine) or M2 (atrial) selective (AF DX 116) drugs. These data tentatively suggest the involvement of an M2 (ileal) type muscarinic receptor. Potency was lower for quaternary structures, probably due to impaired corneal penetration. The potency of pirenzepine and telenzepine was increased 60-fold at low pH following topical administration. Acid induced corneal damage does not appear to account for this potency shift as the effects of scopolamine and several agonists (oxotremorine, pilocarpine and McNA-343) were not substantially altered by acid media. For pirenzepine the potency shift appears to be related to protonation of the second amino group (N1) in the piperazine tail (pKa = 2.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The relative potencies of cholinomimetics and muscarinic antagonists on the rat iris in vivo: effects of pH on potency of pirenzepine and telenzepine. 324 89

1 The acetyl, phenylacetyl, and diphenylacetyl esters of 4-hydroxyquinuclidine and their methiodides have been prepared.2 4-Diphenylacetoxyquinuclidine methiodide has higher affinity for muscarinic receptors than 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP methiodide) but it is less selective. At 30 degrees C its affinity for receptors in ileum is about 5 times that for receptors in atria, a difference similar to that found with diphenylacetoxytrophine methiodide. With 4-DAMP methiodide affinity for receptors in the ileum is over 10 times that for receptors in atria.3 4-Diphenylacetoxyquinuclidine methiodide has higher affinity for muscarinic receptors than 3-diphenylacetoxyquinuclidine hydrochloride or its methiodide.4 4-Acetoxyquinuclidine hydrochloride has less than one-hundredth of the activity of 3-acetoxyquinuclidine hydrochloride (acecyclidine) on guinea-pig ileum, atria, and rat fundus: however, 4-acetoxyquinuclidine methiodide is consistently more active than its 3-isomer, though it is only about 1/25 times as active as acecyclidine.5 4-Acetoxyquinuclidine hydrochloride is only a poor substrate for electric eel acetylcholinesterase: its affinity is similar to that of acecyclidine but it is greatly reduced by methylation.6 The relations between the structure and activity of the agonists are very different from the relations between the structure and affinity of the antagonists, which supports the view that agonists and antagonists bind to different conformations of the muscarinic receptor.
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PMID:The actions of some esters of 4-hydroxyquinuclidine on guinea-pig ileum, atria and rat fundus strip. 713 2

1. Experiments were designed to characterize the subtype(s) of endothelial muscarinic receptor that mediate(s) endothelium-dependent relaxation and contraction in the aorta of spontaneously hypertensive rats (SHR). 2. Rings of SHR aorta with endothelium were suspended in organ baths for the measurement of isometric force. Ecothiopate (an inhibitor of acetylcholinesterase) was present throughout the experiments. Endothelium-dependent contraction to acetylcholine was studied in quiescent aortic rings in the presence of NG-nitro-L-arginine (to prevent the formation of nitric oxide). Endothelium-dependent relaxation to acetylcholine was obtained during contraction to phenylephrine and in the presence of indomethacin (to inhibit cyclo-oxygenase activity). Responses to acetylcholine were assessed against the non-preferential muscarinic receptor antagonist, atropine, and the preferential antagonists pirenzepine (M1), methoctramine (M2) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M3). 3. The potency of acetylcholine in inducing endothelium-dependent contraction was 6.54 +/- 0.07 (EC50). Atropine, pirenzepine, methoctramine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent contraction to acetylcholine. The pA2 values for these muscarinic receptor antagonists were estimated from Arunlakshana-Schild plots to be (-log M) 9.48 +/- 0.07, 6.74 +/- 0.22, 6.30 +/- 0.20 and 9.39 +/- 0.22 respectively. The potency of acetylcholine in inducing endothelium-dependent relaxation was 7.82 +/- 0.09 (IC50). Atropine, pirenzepine and 4-DAMP displayed competitive antagonism towards the endothelium-dependent relaxation to acetylcholine but methoctramine had no effect. The pA2 values for atropine and 4-DAMP for the relaxation to acetylcholine were estimated from Arunlakshana-Schild plots to be (-log M) 9.15 +/- 0.23 and 9.63 +/- 0.28, respectively. These results suggest that the muscarinic M3 receptor subtype mediates both endothelium-dependent relaxation and contraction to acetylcholine in SHR aorta.
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PMID:Mediation by M3-muscarinic receptors of both endothelium-dependent contraction and relaxation to acetylcholine in the aorta of the spontaneously hypertensive rat. 807 71

Cholinomimetic agents increase blood pressure and heart rate via central muscarinic cholinoceptors in various species. It was reported that i.c.v. injection of the muscarinic M1 and M3 cholinoceptor selective antagonist, 4-DAMP (4-diphenylacetoxy-N-methyl-piperidine methiodide), inhibited the pressor response to physostigmine, while the M1 selective antagonist, pirenzepine, was ineffective. In the present study, the involvement of muscarinic M2 cholinoceptors in central cholinergic hypertension and tachycardia was investigated. Physostigmine (10-80 micrograms/kg i.v.), a cholinesterase inhibitor, and oxotremorine (20-40 micrograms/kg i.v.), a direct muscarinic cholinoceptor agonist, caused a dose-dependent increase in blood pressure. Additionally, physostigmine induced dose-dependent tachycardiac responses. I.c.v. administration of the muscarinic M2 cholinoceptor antagonists, AF-DX 116 and methoctramine, inhibited both physostigmine (60 micrograms/kg) and oxotremorine (20 micrograms/kg)-induced pressor responses at their lower doses used in this study (100 nmol/rat and 10 nmol/rat, respectively). These findings indicate the partial involvement of postsynaptic muscarinic M2 cholinoceptors. The higher doses of the antagonists (AF-DX 116,300 nmol/rat and methoctramine 30 nmol/rat) potentiated the blood pressure increase due to physostigmine but did not affect that due to oxotremorine. The physostigmine-induced tachycardiac responses were influenced similarly by these antagonists. These results suggest the presence and tonic influence of presynaptic inhibitory muscarinic M2 cholinoceptors.
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PMID:Central muscarinic M2 cholinoceptors involved in cholinergic hypertension. 811 94

The effect of ad libitum dietary exposure (as occurs in the field) to parathion for 14 d was investigated on the muscarinic acetylcholine receptor (mAChR) in brains and submaxillary glands of adults of a field species, the white-footed mouse Peromyscus leucopus. Immunoprecipitation using subtype selective antibodies revealed that the relative ratios of the m1-m5 mAChR subtypes in Peromyscus brain were similar to those in rat brain. There was little variability in acetylcholinesterase (AChE) activity in control mice brains but large variability in 39 exposed mice, resulting from differences in food ingestion and parathion metabolism. Accordingly, data on radioligand binding to mAChRs in each mouse brain were correlated with brain AChE activity in the same mouse, and AChE inhibition served as a biomarker of exposure reflecting in situ paraoxon concentrations. Exposure to parathion for 14 d reduced maximal binding (Bmax) of [3H]quinuclidinyl benzilate ([3H]QNB), [3H]-N-methylscopolamine ([3H]NMS), and [3H]-4-diphenylacetoxy-N-methylpiperidine methiodide ([3H]-4-DAMP) by up to approximately 58% without affecting receptor affinities for these ligands. Maximal reduction in Bmax of [3H]QNB and [3H]-4-DAMP binding occurred in mice with highest AChE inhibition, while equivalent maximal reduction in Bmax of [3H]NMS occurred in mice with only approximately 10% AChE inhibition, without further change at higher parathion doses. This is believed to be due to the hydrophilicity of [3H]NMS, which limits its accessibility to internalized desensitized receptors. In submaxillary glands (mAChRs are predominantly m3 subtype), there were significant dose-dependent reductions in [3H]QNB binding and m3 mRNA levels in exposed mice, revealed by Northern blot analyses. The reduction in m3 receptors is suggested to result mostly from reduced synthesis at the transcription level, rather than from translational or posttranslational events. The data suggest that down-regulation of mAChRs occurs after dietary exposure for 14 d to sublethal concentrations of parathion in a field rodent species, and that significant though incomplete recovery in AChE and mAChRs occurs in 7 d following termination of exposure.
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PMID:Down-regulation of muscarinic receptors and the m3 subtype in white-footed mice by dietary exposure to parathion. 835 Mar 85


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