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)

The transsynaptic induction of the monoamine transporter present on the membrane of chromaffin granules was studied in primary cultures of dissociated bovine adrenomedullary cells submitted to a chronic secretory stimulation. The amount of the vesicular monoamine transporter was assayed by binding of the specific ligand [3H]-dihydrotetrabenazine. After several days of incubation in the presence of high potassium, the concentration of [3H]-dihydrotetrabenazine binding sites was increased by a 1.5-2.5 factor. This increase was smaller in the presence of the cholinergic agonist carbachol. The long-term inductions of the vesicular monoamine transporter, of tyrosine hydroxylase, and of acetylcholinesterase were of similar magnitude. Under the same conditions, we found no variation in either the activities of other catecholamine biosynthetic enzymes (dopamine beta-hydroxylase and DOPA decarboxylase), or in metabolic enzymes such as lactate dehydrogenase and cytochrome c oxidase, and a decrease in the cellular content of chromogranin A and cytochrome b-561. The induction of the vesicular monoamine transporter was inhibited by the calcium channel antagonists, fluspirilene and nifedipine, and was increased by the agonist Bay K 8644. It was abolished by cycloheximide and actinomycin D. These results indicate that calcium entry into chromaffin cells increases the synthesis of the vesicular monoamine transporter, presumably by transcriptional activation. Elevation of intracellular cyclic AMP concentration or activation of protein kinase C also induced an increase in the expression of the vesicular monoamine transporter. Our results confirm that components of storage vesicle membranes are differentially regulated in response to secretory stimulation, as are several cytosolic or intravesicular soluble proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the chromaffin granule catecholamine transporter in cultured bovine adrenal medullary cells: stimulus-biosynthesis coupling. 127 22

The effect of the calcium antagonists omega-conotoxin GVIA, verapamil, gallopamil and diltiazem was investigated on in vitro bronchial smooth muscle contraction in the rat induced by the nerve agent soman. Soman inhibits the acetylcholinesterase activity irreversibly. The effect of the calcium channel antagonists on contractions induced by electrical field stimulation and carbachol was also investigated, in order to elucidate the mechanism by which calcium antagonists inhibit the soman induced contraction. omega-Conotoxin GVIA reduced the bronchial smooth muscle contraction induced by electrical field stimulation with an almost complete inhibition at approximately 1.0 x 10(-6) M. The soman induced contraction was only inhibited by 15% at a concentration of 3.0 x 10(-6) M omega-conotoxin GVIA. The organic calcium antagonists verapamil, gallopamil and diltiazem reduced both electrically and soman induced smooth muscle contraction. Complete inhibition of the contractions induced by soman was achieved at 1.4 x 10(-4) M for verapamil and gallopamil, while diltiazem inhibited the contraction to 7% of control at 1.4 x 10(-4) M. Verapamil, gallopamil and diltiazem increased the EC50 for carbachol significantly, while omega-conotoxin GVIA had no effect. None of the calcium antagonists had any effect on the maximal contraction induced by carbachol. Verapamil, gallopamil and diltiazem blocked, however, sub-maximal contractions induced by carbachol (10(-7)-10(-5) M) resulting in a right-shift of the dose response curve. The results show that omega-conotoxin GVIA inhibits the calcium-dependent release of acetylcholine which causes contraction of airway smooth muscle, while it has no effect on smooth muscle contraction induced by soman.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of calcium antagonists (omega-conotoxin GVIA, verapamil, gallopamil, diltiazem) on bronchial smooth muscle contractions induced by soman. 140 18

The dihydropyridine calcium channel antagonist nifedipine causes marked reductions in the amounts of acetylcholinesterase (AchE) molecular forms in primary tissue cultures of avian pectoral muscle. These reductions are time-dependent, requiring passage of 3 h prior to any observable response, dose-dependent, with principal actions occurring in the 1-100 nM range, are greater on the 7 S and 19 S forms than on the 11.4 S form, and, based on susceptibility of AchE to irreversible inhibition by a cationic inhibitor, occur almost exclusively with intracellular AchE coincident with a 2-fold reduction in the rate of secretion. The effects are markedly more pronounced in skeletal muscle than in neurons and differ from those observed for verapamil, diltiazem, and the calcium ionophore A23187. These reductions are incompatible with accelerated protein degradation, alterations in posttranslational processing and assembly in the Golgi complex, or enhanced loss of enzyme to the medium, but instead indicate that nifedipine causes a reduction in AchE biosynthesis. Since AchE forms are thought to arise from a single gene, these findings imply a linkage in skeletal muscle between transcription and posttranscriptional processing of mRNA and ligand occupation of the dihydropyridine receptor.
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PMID:Dihydropyridine receptor regulation of acetylcholinesterase biosynthesis. 216 16

Alpha-actinin is a muscle protein located along the Z-disc. Incubation of frog muscle with the calcium ionophore, A23187, can decrease the immunogold labelling of alpha-actinin. Pyridostigmine (PYR) is an inhibitor of acetylcholinesterase, which causes disruption of Z-discs only in the region of the motor endplate. This is probably due to excess influx of calcium ions, leading to activation of proteases. Pretreating animals with the calcium channel blocker diltiazem can significantly reduce damage to the Z-discs at the motor endplate caused by PYR. It was of interest to determine whether the distribution of alpha-actinin had been altered following PYR administration and whether diltiazem could prevent those changes. There was less alpha-actinin labelling at the motor endplate compared to away from this region for all treatment groups. Animals administered diltiazem showed less labelling compared to PYR, but with no disruption of Z-discs at the motor endplate following diltiazem. Pretreatment with diltiazem reduced the incidence of Z-disc damage, but the degree of alpha-actinin labeling at the endplate was less than that seen with diltiazem alone. The greater effect seen at the endplate implies that neuromuscular activity is an important factor. The drugs may be causing a reduction in alpha-actinin labelling by different mechanisms.
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PMID:Calcium channel blocker influences the density of alpha-actinin labeling at the rat neuromuscular junction. 235 47

In the substantia nigra, acetylcholinesterase may have a non-classical function unrelated to cholinergic transmission. Acetylcholinesterase is released from the dendrites of dopamine-containing nigrostriatal neurons and has a subsequent action on these cells, independent of hydrolysis of acetylcholine. The aim of this study was to explore further the precise nature of this "non-cholinergic" action of acetylcholinesterase. Acetylcholinesterase was pressure-ejected in the vicinity of the dendrites of putative nigrostriatal neurons in vitro, in near-physiological amounts, and the effects of this treatment on neuronal membrane properties were investigated. It was found that acetylcholinesterase reversibly hyperpolarized the nigrostriatal cell membrane independent of sodium and calcium channel blockade. Acetylcholinesterase pretreated with an irreversible inhibitor (Soman) of its classical catalytic site produced the same hyperpolarizing effect: however, butyrylcholinesterase, which hydrolyses acetylcholine, was inefficacious. These effects persisted in the presence of the dopamine receptor antagonist sulpiride. It is suggested the acetylcholinesterase can facilitate the generation of a long-duration conductance, which enhances the firing of nigrostriatal cells if the neuron is first hyperpolarized. Hence the action of acetylcholinesterase would be to modulate inputs. These actions are independent of direct interaction with acetylcholine and dopamine systems. Hence, in the substantia nigra, acetylcholinesterase might serve as a "neuromodulatory" secretory protein.
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PMID:Pressure ejection of acetylcholinesterase within the guinea-pig substantia nigra has non-classical actions on the pars compacta cells independent of selective receptor and ion channel blockade. 246 38

The adverse reactions seen following administration of neuromuscular blocking agents are mainly cardiovascular. Due to the lack of specificity for the nicotinic receptor at the neuromuscular junction, these agents may interact with receptors in autonomic ganglia and muscarinic receptors in the heart. Furthermore, muscle relaxants may have histamine-releasing properties. The cardiovascular effects vary with potency and specificity of the drug, depending mainly on the chemical structure. Pancuronium, fazadinium and especially gallamonium block cardiac muscarinic receptors, and tachycardia may be seen. Atracurium, metocurine and in particular d-tubocurarine have histamine-releasing properties and may cause flushing, hypotension and tachycardia. Vecuronium has no effect on the cardiovascular system. The effect of succinylcholine on heart rate differs between children, where bradycardia is seen, and adults in whom tachycardia may follow. However, bradycardia may occur in adults following a single dose. Succinylcholine increases plasma potassium, especially in patients with nerve damage, and arrhythmias may be observed. The neuromuscular adverse effects of succinylcholine, such as fasciculations and increased gastric and intraocular pressure, may be prevented by precurarisation. Many drugs interact with neuromuscular blocking agents and there is often a potentiation of the neuromuscular effect. This is of clinical importance in the case of antibiotics, inhalational anaesthetics, lithium and cyclosporin. Difficulty in reversing the block may occur with calcium channel blockers and polymyxin. However, some drugs, such as phenytoin, carbamazepine and lithium, may cause resistance to neuromuscular blocking agents. Furthermore, clinically important interactions exist between individual neuromuscular blocking drugs. Precurarisation with a non-depolarising drug prolongs the onset of succinylcholine, and conversely a prolonged effect of non-depolarising drugs is seen following succinylcholine. The effect of succinylcholine is markedly prolonged if the drug is administered during recovery from pancuronium blockade or following neostigmine for reversal. Succinylcholine is hydrolysed by plasma cholinesterase, and drugs which decrease the activity of this enzyme may produce a prolonged block, i.e. contraceptive pills, cyclophosphamide, echothiopate and organophosphate.
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PMID:Adverse reactions and interactions of the neuromuscular blocking drugs. 268 31

Inhibition of the enzyme, acetylcholinesterase (AChE), at the neuromuscular junction by pyridostigmine (PYR) results in breakdown of the postjunctional folds and dissolution of the Z-discs. It is hypothesized that excess activation of the acetylcholine (ACh) receptors by unhydrolyzed ACh results in a large influx of calcium ions. This could possibly lead to the activation of calcium-dependent proteases, resulting in the observed myopathy. Pretreatment with the calcium channel blocker, diltiazem, followed by administration of both PYR and the calcium blocker resulted in a significant reduction in the extent of muscle damage due to PYR alone. In order to ascertain whether the calcium blocker could reverse the myopathy previously induced by PYR, the AChE inhibitor was administered first, resulting in significant muscle damage, followed the next day by diltiazem. After 7 days of diltiazem treatment, with continued administration of PYR, the calcium blocker significantly reduced the myopathy at the neuromuscular junction. The results are discussed in terms of possible clinical application of diltiazem in neuromuscular diseases (i.e. muscular dystrophy).
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PMID:Calcium channel blocker reverses anticholinesterase-induced myopathy. 279 Apr 49

Radiation inactivation was employed to measure the molecular size of calcium channels in guinea-pig skeletal muscle membranes, labelled by the potent 1,4-dihydropyridine calcium antagonist [3H]nimodipine. The molecular size was decreased when the membranes were preincubated and assayed with d-cis-diltiazem, a calcium channel blocker, which is structurally unrelated to the 1,4-dihydropyridines. d-cis-Diltiazem, which is a positive heterotropic regulator of 1,4-dihydropyridine calcium channel binding in vitro, reduced the molecular size from 178 000 to 111 500. 1-cis-Diltiazem, the diastereoisomer, which is devoid of calcium antagonistic action, did not decrease the molecular size of the 1,4-dihydropyridine binding site. Neither diastereoisomer affected the molecular size of the membrane-bound acetyl-cholinesterase, indicating that a stereospecific interaction with the calcium channel structure is the basis for these observations. It is concluded that this decrease in size is indicative of the oligomeric nature of the calcium channel and that calcium channel blockers, acting via different, but interacting drug receptor sites, induce different conformations of the channel structure, resulting in altered conductivity for ions.
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PMID:Calcium channels: evidence for oligomeric nature by target size analysis. 631 98

The effect of elevated extracellular potassium on acetylcholine receptor synthesis was studied in chick embryonic muscle cultures. At physiological ionic strength, potassium chloride, in the 3.3 to 50 mM range, gave rise to a complex dose-response curve whose prominent features are a considerable reduction of receptor appearance rate at 20 mM and a more than 2-fold increase at higher concentrations. The effect of potassium chloride on receptor synthesis appears to be fairly specific: neither was there a duplication of its effect by other electrolytes or solutes, nor did it alter total protein synthesis or receptor stability by more than 30% at any concentration tested; cellular acetylcholinesterase levels actually declined with increasing KCl concentrations. In order to explore the mechanism of the potassium effect, tetrodotoxin (10(-6) M), veratridine (3 X 10(-6) M), D-600 (1.6 X 10(-5) M), and ryanodine (3 X 10(-7) M) were tested in the presence of various concentrations of potassium. Sodium channel toxins as well as calcium effectors modified the potassium response. Based on these findings we propose that the effects of potassium are due to: (a) cessation of spontaneous muscle activity upon raising KCl from 3 to 10 mM; (b) depolarization of the muscle membrane and persistent activation of a calcium channel as concentration is raised from 10 to 20 mM; (c) finally, inactivation or desensitization of the calcium channel, or some other signaling element proximal to the sarcoplasmic reticulum, upon further depolarization.
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PMID:Extracellular potassium and the regulation of acetylcholine receptor synthesis in embryonic chick muscle cells. 683 74

The monoethylcholine aziridinium ion, AF64A, (3 nmol in 1 microliter) or artificial CSF (1 microliter) was infused unilaterally into the right dorsal lateral ventricle of male adult rats. Treatment with the L-type calcium channel antagonist, nimodipine (70 micrograms/kg b.wt.) or its vehicle was administered beginning before and for seven days following surgery. The infusion of AF64A reduced spontaneous alternation rates in the T-maze when compared to CSF and sham infused animals. AF64A-treated animals also took longer to reach the goal area in a complex maze task on specific trials relative to CSF and sham-infused animals. Locomotion and habituation to the open field did not differ between surgery groups. Unilateral AF64A significantly depleted acetylcholinesterase (AChE) positive terminals in the ipsilateral hippocampus and cell bodies in the ipsilateral medial septal area (MSA). Receptors for nerve growth factor (NGF-R), often colocalized with cholinergic cell bodies and terminals, also were depleted in the ipsilateral MSA of AF64A infused animals. Treatment with nimodipine did not have a neuroprotective effect on AF64A animals in either behavioral or histological results. However, some degree of protection was found in the vehicle-treated rats. This effect was likely a consequence of the stress of the injection procedure rather than the content of the vehicle, largely polyethylene glycol 400. Nimodipine-treated animals, regardless of surgery group, exhibited fewer emotional responses and had lower spontaneous alternation rates than untreated animals. The behavioral alterations found in the nimodipine groups are most easily explained in terms of altered emotionality. Overall our findings indicate that AF64A is a potent cholinotoxin that can selectively eliminate the ipsilateral septohippocampal cholinergic system when unilaterally infused into the lateral ventricle. It is possible that the mechanism of action of AF64A, like other nitrogen mustard analogues, involves disruption of basic processes involved in protein synthesis and DNA activities. Because of this, the toxic effects of the aziridinium mustard are independent of extracellular calcium and thus may not be susceptible to protection by calcium channel antagonists.
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PMID:Behavioral and neuroanatomical consequences of a unilateral intraventricular infusion of AF64A and limitations on the neuroprotective effects of nimodipine. 792 42


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