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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetylcholine can be released from parasympathetic nerve endings in rat atria by 57 mM K+ depolarization or by electrical field stimulation. We have studied the presynaptic modulation of [3H]acetylcholine release from superfused rat atria prelabeled with [3H]choline. Exogenous acetylcholine and the specific muscarinic agonist oxotremorine inhibit the stimulation-induced overflow of [3H]acetylcholine into the superfusion medium. The half-maximal inhibitory concentration (IC50) of oxotremorine is 0.3 microM. The cholinesterase inhibitor neostigmine also decreases K+-stimulated [3H]acetylcholine overflow, whereas the muscarinic antagonist atropine enhances the overflow of [3H]acetylcholine. These data suggest that acetylcholine release in atria is modulated through negative feedback by the endogenous transmitter. The sympathetic adrenergic neurotransmitter norepinephrine and the neurohormone epinephrine also inhibit the overflow of [3H]acetylcholine by approximately 60%. The IC50 values for the inhibitory effects of these catecholamines are 6.3 and 2.2 microM, respectively. The inhibitory effect of norepinephrine is blocked by the alpha-adrenergic receptor antagonist yohimbine but not by the beta-adrenergic receptor antagonist propranolol. We suggest that presynaptic muscarinic and alpha-adrenergic receptors participate in the physiological and pharmacological control of cardiac parasympathetic activity.
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PMID:Presynaptic modulation of acetylcholine release from cardiac parasympathetic neurons. 285 26

1. Male weanling swine were injected daily for up to 14 days with the organophosphate cholinesterase inhibitors, diisopropylfluorophosphate (DFP) or sarin. The clinical signs of poisoning disappeared or were attenuated by 7 days after starting the DFP treatment, indicating the development of tolerance to DFP toxicity. 2. A significant decrease in acetylcholinesterase activity (85-98%) occurred over the course of this treatment followed by a decrease in the maximal density (Bmax) of [3H] quinuclidinyl benzilate ([3H]QNB) and [3H] N-methylscopolamine ([3H]-NMS) binding sites in isolated cells. The affinity of the muscarinic receptors (KD) for [3H]QNB and [3H]NMS binding, however, remained unaffected. 3. Dose-response curves for ACh-induced increase in isometric tension of tracheal smooth muscle (TSM) showed a leftward shift from control, 2 h after DFP injection. Twenty-four hours after the last DFP treatment, for animals receiving 1 or up to 14 daily injections of DFP, all the dose-response curves were shifted to the left to approximately the same ACh sensitivity when compared with that for control tissue. 4. In vitro treatment of the muscle with 10(-4) M DFP shifted the dose-response curves leftward, in both control and injected animals, and rendered the muscles from control, 1- and 3-day injected animals sensitive to ACh concentrations as low as 10(-10) M. Sensitivity to 10(-10) M ACh was eliminated by carefully cleaning the smooth muscle of adherent connective tissue containing nerves and ganglia and after subacute treatment of swine for 7 days with DFP. DFP-induced spontaneous contractions were also eliminated by careful cleaning. 5. Subacute DFP treatment caused a small leftward shift in the dose-response curve for bethanechol at 2 h and a rightward shift at 1,3 and 7 days, compared to controls. 6. Dose-response curves for K+ were shifted to the right after 1 and 3 days of DFP treatment, but shifted back towards the control after 7 days of treatment. The muscle cells were hyperpolarized by approximately 5 mV after 7 days of DFP or sarin injections. The membrane potential was slightly more sensitive to changes in K+ concentration after 7 days of sarin injection. 7. Subacute treatment of swine with organophosphates modifies the response of neural elements in swine TSM to ACh. Chronic cholinesterase inhibition causes a reduction in the sensitivity of the neural elements to ACh. The decrease in muscarinic receptor density which occurs with chronic cholinesterase inhibition is not sufficient to explain tolerance to organophosphates since TSM maintains an almost normal responsiveness to ACh.
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PMID:Contractile responses of tracheal smooth muscle in organophosphate-treated swine: 1. Agonist changes. 290 99

The sequence of events leading to the formation of the NMJ based on the data presented in this chapter from rat, chick, and Xenopus muscle can be divided into three developmental stages, as shown in Table I. The essential components of the NMJ are acquired early. Acetylcholine is present and can be released from the growing nerve. Acetylcholine receptors are present in the muscle membrane and are functional even at the earliest times. These components of the junction--ACh release and functional ACh receptors--can develop independently of each other; i.e., cell culture studies have shown that nerve cells are capable of releasing ACh before their growing tips have come into contact with the postsynaptic muscle membrane. Conversely, muscle cells grown without nerve synthesize and incorporate in their membranes functional ACh receptors. This situation ensures that functional (table; see text) contacts can occur even at the earliest times. Local accumulation of ACh receptors is also detected at the earliest times of junction formation. Although cell culture studies have demonstrated that receptors can aggregate in the absence of nerve, it would appear that the nerve plays an important role in directing where the highest density of receptors will be localized. Acetylcholinesterase, identified both histochemically and electrophysiologically, occurs at the presumptive NMJ shortly after synaptic transmission and receptor clustering have begun, suggesting that these events may play a role in localizing cholinesterase. Although the studies on rat and chick muscle support this view, development of AChE on Xenopus muscle does not require prior exposure to nerve or muscle activity. The ultrastructural features characteristic of the adult NMJ also do not become apparent until after synaptic transmission and receptor clustering have been seen. However, detection of small regions of specialization could be easily overlooked at the ultrastructural level, particularly if the tissue has not been serially sectioned. The young tissue is more fragile (Gordon et al., 1974) and may be more susceptible to mechanical damage or alterations from the fixation procedures (Kullberg et al., 1977). For these reasons, results pertaining to when the ultrastructural specializations occur are difficult to interpret and must await identification of these structures by other means. A number of other changes occur at the NMJ late in development: (1) ACh receptors become metabolically more stable, (2) there is a conversion in the kinetics of the ACh receptor channel, and (3) junctional folds become apparent. The extent to which these changes occur varies among the different organisms discussed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Formation of the vertebrate neuromuscular junction. 290 8

Acetylcholine content of blood and cholinesterase activity in blood and tissues of albino rats were studied at different time-intervals after gamma-irradiation with doses of 12.9 and 25.8 mC/kg. Cholinergic processes were found to change with the development of radiation dose.
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PMID:[Cholinergic processes as affected by small doses of radiation on the host]. 292 80

1. We have shown that all cholinesterase (ChE) inhibitors, in addition to their well-known anti-ChE activity, have multiple effects on the nicotinic acetylcholine receptor-ion channel (AChR) macromolecule resulting from interactions with the agonist recognition site and with sites located at the ion channel component. Activation, competitive antagonism and different types of noncompetitive blockade occurring at similar concentration ranges and contributing in different proportions result in complex and somewhat unpredictable alterations in AChR function. The question is now raised as to how each effect of these compounds contributes to their antidotal property against organophosphorus (OP) poisoning, and what set of actions makes one reversible ChE inhibitor a better antidote. Many lines of evidence support the importance of direct interactions with various sites on the AChR: 1) morphological and toxicological studies with (+) physostigmine showed that anti-ChE activity is not essential to protect animals against toxicity by irreversible ChE inhibitors; 2) (-)physostigmine is far more effective against OP poisoning; 3) open channel blockers such as mecamylamine with no significant anti-ChE activity enhance the protective action of (-)physostigmine; 4) neostigmine, pyridostigmine, (-)physostigmine and (+)physostigmine showed qualitatively and quantitatively distinct toxicity and damage to endplate morphology and function. 2. In prophylaxis and during the very early phase of OP poisoning, carbamates, especially (-)physostigmine combined with mecamylamine and atropine, could protect almost 100% of the animals exposed to multiple lethal doses of OPs. Electrophysiological data showed that (-)physostigmine, among several reversible ChE inhibitors, showed greater potency in depressing both endplate current (EPC) peak amplitude and tau EPC. Therefore, concerning neuromuscular transmission, it seems that the higher the potency of a drug in reducing endplate permeability, the better is its protection against OP toxicity. A reversible open channel blockade combined with some agonist property helps to decrease the effect of ACh at its agonist site and to reduce the ion permeability of open channels. It should be pointed out that, during the later phase of OP poisoning, AChR desensitization should be most prevalent. Thus, a drug that can remove the AChR from this rather irreversible state to a more reversible blocked state should be a better protector. Indeed, oximes such as 2-PAM and a more potent analog, HI-6, produce multiple alterations in AChR function that comprise increased channel activation and open-channel blockade.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structure-activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex. 307 41

The fractional increase in ACh responses that occurs at the beginning of each train of iontophoretically applied ACh pulses has been examined at the frog neuromuscular junction at room temperature, in the presence of active cholinesterase, during desensitization produced by a rapid sequence (every 20 s) of short (5 Hz, 5 s) iontophoretic trains of ACh. The fractional increase in ACh responses, which is used as an indicator of postsynaptic potentiation, becomes progressively greater with ACh application, often markedly (greater than 100%), although ACh responses are greatly reduced (as much as 90%) owing to desensitization. Clearly postsynaptic potentiation can exist concomitantly with desensitization. In addition, the dose-response curve is shifted to the right and its maximal response is diminished. The shift in the dose-response curve to the right, which can explain greater postsynaptic potentiation, is unlikely to be caused by accumulation of "monoligand-bound ACh receptor complexes," since experiments were done with active cholinesterase. The shift probably results from a greater number of desensitized receptors which, because of their large affinity for ACh molecules, serve as "high affinity traps." A small decrease of the maximal dose-response suggests only a small fractional decrease in the number of activable receptors, whereas a large shift to the right indicates a large fractional increase in the number of desensitized receptors. It appears that prior to ACh application only a small fraction of all receptors are desensitized. Alternatively, the shift to the right occurs because the cooperative action of ACh on receptors increases during desensitization.
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PMID:Postsynaptic potentiation and desensitization in frog neuromuscular junction. 326 5

Elevation of extracellular potassium concentration ([K+]o) in cutaneous pectoris neuromuscular junction from 2 to 20 mM slowly increased the variability of the amplitudes of miniature end-plate currents (AMEPC-s), (coefficient of variation of AMEPC-s increased by 73%). Mean AMEPC-s, however, decreased but not markedly (by 14%). Comparable MEPC changes were observed when [K+] was raised in the presence of choline chloride (50 microM), arguing that MEPC changes were not primarily due to a lower and less uniform vesicular filling. Channel kinetics were not altered by high [K+]o, since the time constant of decay of miniature end-plate currents (TMEPC-s) did not change. Acetylcholine clearance from the synaptic cleft, however, appeared to be faster in high [K+]o since with cholinesterase blocked throughout, TMEPC-s were shortened. The changes of spontaneous quantal discharge induced by high [K+]o can be almost entirely explained by altered spatial distribution of vesicular release if, as recent reports suggest, at high [K+]o, exocytosis appears randomly not only at but also in between the active zones. However, relatively greater frequency of large MEPCs suggests that in high [K+]o some, and possibly all, quanta are filled above normal levels. High [Ca2+]o appears to counteract, although not always completely, all changes in spontaneous quantal secretion induced by high [K+]o. It is possible that high [Ca2+]o reverses the changes in the spatial distribution of vesicular release induced by high [K+]o. However, high [Ca2+]o also leads to other pre- and postsynaptic changes.
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PMID:Changes in miniature end-plate currents due to high potassium and calcium at the frog neuromuscular junction. 326 41

The properties of muscarinic acetylcholine receptors (mAChR) on tracheal explants and isolated submucosal gland cells were determined using [3H]quinuclidinyl benzilate ([3H]QNB) and N-[3H]methylscopolamine ([3H]NMS) as ligands. Analysis of competitive displacement of ([3H]NMS binding by pirenzepine demonstrated the presence of M1- (27 +/- 2%) and M2G- (73 +/- 2%) receptors on isolated tracheal submucosal gland cells (TSGC's) in control. Daily administration of diisopropylfluorophosphate (DFP) inhibited cholinesterase activity by greater than 95%. After 7 days of DFP treatment, [3H]QNB binding to intact TSGC's decreased from 14.2 +/- 0.6 to 6.3 +/- 0.8 fmol/10(6) cells; similarly, [3H]NMS binding fell from 8.1 +/- 1.9 to 2.0 +/- 0.8 fmol/10(6) cells. The loss of mAChR's was predominantly of the M2G subtype with the relative proportion dropping to 33%. In addition, 90% of the receptors assumed the high-affinity state for carbachol displacement of [3H]NMS. Mucus secretion was quantitated by measuring the release of 3H-labeled mucus macromolecules from explants of tracheal submucosal glands and isolated cells. Acetylcholine (ACh), 2 X 10(-5) M, stimulated mucus secretion by 2.5 and 2.3 times the basal rate, respectively. Elimination of acetylcholinesterase (AChe) by DFP increased the ACh sensitivity by 18- and 5-fold. Tracheal explants or TSGC's obtained 2 h after an in vivo DFP treatment showed a 6- and 3-fold ACh stimulation. This ACh sensitivity decreased during the continued daily dosing with DFP such that only a 1.3- and 1.1-fold ACh stimulation was apparent after 7 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic stimulation of submucosal glands in swine trachea. 335 38

The density and distribution of junctional and perijunctional ACh receptors (AChR) were studied in young (8-12 months) and old (24-25 months) C57 mice to determine: (1) if increased amplitude of spontaneous postsynaptic potentials previously reported in old C57 muscle was due to increased junctional AChR; (2) if increased extrajunctional AChR would be found in association with previously reported nerve terminal complexity; and (3) if extrajunctional AChR was present as in disused or denervated muscle. Microdissection of individual muscle fibers combined with I125-alpha-bungarotoxin labeling, gamma counting, measurement of surface area, cholinesterase stains, and autoradiography were used to obtain the results. In both young and old mice there was a sharp gradient in AChR between the end-plate and the perijunctional region. End-plate AChR densities and total AChR per end-plate were the same at old and young end-plates, as were perijunctional values. Thus, neither end-plate nor extrajunctional AChR density changes with age. An increased mepp amplitude reported previously in old CB57 animals must be due to other factors. The perijunctional AChR in old mice show no changes characteristic of disuse or denervation, or those which might give rise to the observed nerve terminal complexity.
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PMID:Acetylcholine receptors at mature and aged mouse neuromuscular junctions. 339 94

In the presence of a cholinesterase inhibitor to prevent hydrolysis and atropine to block muscarinic cholinergic receptors, [3H]acetylcholine ([3H]ACh) binding to human brain membranes showed highest levels of nicotinic binding sites in the thalamus. [3H]ACh, in the presence of atropine, binds to heterogeneous high-affinity binding sites in human thalamus. Scatchard analysis of the binding gave a Kd of 0.58 nM and a Bmax of 3.3 pmol/g protein for the 'super high-affinity' site and a Kd of 27 nM and a Bmax of 70 pmol/g protein for the 'high-affinity' site. Moreover, in competition studies nicotinic agonists such (-)-nicotine and carbachol displaceable [3H]ACh-specific binding sites consist of both a high- and a low-affinity population of sites. These results indicate that highest levels of [3H]ACh binding in human brain were found in the thalamus. Moreover, the human thalamus was found to have multiple high-affinity nicotinic agonist sites.
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PMID:[3H]acetylcholine nicotinic recognition sites in human brain: characterization of agonist binding. 344 12


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