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)

Direct interactions of the bispyridinium oxime HGG-12 with muscarinic acetylcholine receptors were investigated in porcine cardiac atrial membranes. Competition binding experiments using the radiolabeled muscarinic receptor antagonist (3H)QNB revealed specific binding of HGG-12 to muscarinic acetylcholine receptors of porcine atrial membranes with a dissociation constant of 3.8 x 10(-7) mol/l. Muscarinic acetylcholine receptor-stimulated binding of the radiolabeled GTP analog (35S)GTP[S] to guanine nucleotide binding proteins (G-proteins) was used to study antagonistic and possible agonistic effects of HGG-12 at muscarinic acetylcholine receptors. HGG-12 completely inhibited carbachol- and oxotremorine-stimulated (35S)GTP[S] binding to pertussis toxin sensitive and insensitive G-proteins in a competitive manner. Inhibition constants (K1) of HGG-12 for blockade of carbachol- and oxotremorine-stimulated GTP[S]-binding (9.7 x 10(-7) mol/l and 1.7 x 10(-6) mol/l, respectively) were higher by about a factor of 100 than those of the muscarinic acetylcholine receptor antagonist atropine. In the absence of muscarinic acetylcholine receptor agonists. HGG-12 by itself had no stimulatory effect on (35S)GTP[S] binding in porcine atrial membranes. The results of this study show that the oxime HGG-12 is a competitive antagonist without intrinsic activity at porcine atrial muscarinic acetylcholine receptors. The stimulatory action of HGG-12 on muscarinic acetylcholine receptors which has been described by several authors is, therefore, suggested to be due to partial inhibition of acetylcholinesterase by the oxime rather than to direct agonism at muscarinic acetylcholine receptors.
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PMID:The oxime HGG-12 as a muscarinic acetylcholine receptor antagonist without intrinsic activity in cardiac membranes. 192 74

Sarcolemmal membranes were isolated from porcine skeletal muscle by modifications of a LiBr-extraction technique. Latency determinations of acetylcholinesterase, ouabain-sensitive p-nitrophenylphosphatase, [3H]ouabain binding, and (Na+ + K+)-ATPase activities indicated that 65-76% of the membranes were sealed inside-out vesicles. The preparations were enriched in cholesterol and phospholipid, and demonstrated adenylate cyclase activity and both cAMP and cGMP phosphodiesterase activities. An indication of the purity of this fraction was that the Ca2+-ATPase activity (0.13 mumol Pi mg-1 min-1 at 37 degrees C) was 3.8% of that of porcine skeletal muscle sarcoplasmic reticulum preparations. Pertussis toxin specifically catalyzed the ADP-ribosylation of a Mr 41,000 sarcolemmal protein, indicating the presence of the inhibitory guanine nucleotide regulatory protein of adenylate cyclase, Ni. An endogenous ADP-ribosyltransferase activity, with several membrane protein substrates, was also demonstrated. The addition of exogenous cAMP-dependent protein kinase or calmodulin promoted the phosphorylation of a number of sarcolemmal proteins. The calmodulin-dependent phosphorylation exhibited an approximate K 1/2 for Ca2+ of 0.5 microM, and an approximate K 1/2 for calmodulin of 0.1 microM. 125I-Calmodulin affinity labeling of the sarcolemma, using dithiobis(succinimidyl propionate), demonstrated the presence of Mr 160,000 and 280,000 calmodulin-binding components in these membranes. These results demonstrate that this porcine preparation will be valuable in the study of skeletal muscle sarcolemmal ion transport, protein and hormonal receptors, and protein kinase-catalyzed phosphorylation.
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PMID:Components of purified sarcolemma from porcine skeletal muscle. 299 26

Although the neurotoxicity of organophosphorus compounds is generally attributed to inhibition of acetylcholinesterase, recent reports have indicated that direct interactions with muscarinic receptors and signal transduction may be an additional mechanism of neurotoxicity. We have previously shown that the organophosphorus insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate (chlorpyrifos) binds directly to muscarinic receptors and inhibits adenylate cyclase of rat striatum. We have further pursued those results in this study by investigating the effect of chlorpyrifos oxon in NG108-15 neuroblastoma-glioma cells and Chinese hamster ovary cells transfected with cDNA for human m2 or m4 muscarinic receptor subtypes. At millimolar concentrations, chlorpyrifos oxon inhibited [3H]QNB binding in all cell lines. Likewise, [3H]CD binding was inhibited in NG108-15 and CHO-Hm2 cells. When the effect of chlorpyrifos oxon on adenylate cyclase was examined, the oxon was found to inhibit adenylate cyclase at millimolar concentrations. Though this effect on cyclase required greater concentrations of oxon than the comparable effect in striatal cells, it displayed the common characteristic of being atropine-insensitive, suggesting that the effect on cyclase was not muscarinic receptor dependent. The inhibition of adenylate cyclase produced by chlorpyrifos oxon was not eliminated in pertussis toxin treated cells, lending further support to the idea that it is not a receptor-mediated event, and suggesting a potential direct interaction of chlorpyrifos oxon with the adenylate cyclase molecule.
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PMID:In vitro effect of chlorpyrifos oxon on muscarinic receptors and adenylate cyclase. 756 87

Cholinergic neurotransmission in the medial pontine reticular formation (mPRF) modulates rapid eye movement (REM) sleep generation. Microinjection of cholinergic agonists and acetylcholinesterase inhibitors into the mPRF induces a REM sleep-like state, and microdialysis data reveal increased mPRF levels of acetylcholine during REM sleep. Muscarinic cholinergic receptors (mAChRs) participate in REM sleep generation, and data suggest that mAChRs of a non-M1 subtype modulate REM sleep generation. The signal transduction pathway activated by m2 and m4 mAChRs involves a pertussis toxin-sensitive G protein, adenylate cyclase (AC), adenosine 3',5'-cyclic monophosphate (cAMP), and protein kinase A (PKA). Therefore, the present study tested the hypothesis that cAMP and PKA within the mPRF modulate the carbachol-induced REM sleep-like state. To test this hypothesis, the mPRF was microinjected with compounds known to facilitate the effects of cAMP (dibutyryl cAMP and 8-bromo-cAMP), stimulate PKA (Sp-cAMP[S]), and inhibit PKA (Rp-cAMP[S]). The results showed that compounds that fostered the intracellular effects of cAMP significantly decreased cholinergic REM sleep, while having no effect on spontaneously occurring REM sleep. These data are consistent with the recent finding that within the mPRF, AC and a pertussis toxin-sensitive G protein modulate cholinergic REM sleep generation. These new data suggest a modulatory role for pontine cAMP and PKA in cholinergic REM sleep regulation.
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PMID:cAMP and protein kinase A modulate cholinergic rapid eye movement sleep generation. 936 9

1. Although peptides are important modulators of synapses, their action on synapse-glia interactions remain unclear. The amphibian neuromuscular junction (NMJ) was used to examine the effects of substance P (SP) on perisynaptic Schwann cells (PSCs), glial cells at the frog NMJ, by monitoring changes in intracellular Ca2+. 2. SP induced Ca2+ responses that were mimicked by the neurokinin 1 receptor (NK-1) agonist septide and with a shorter delay by the SP fragment, SP(6-11). SP and SP(6-11) responses were blocked by NK-1 antagonists SR140333 and LY303870. 3. Ca2+ responses remained unchanged when extracellular Ca2+ was removed but were blocked after pertussis toxin (PTX) treatment, indicating that the receptors were linked to internal stores of Ca2+ via a PTX-sensitive G-protein. 4. The slowly hydrolysable NK-1 agonist [Sar9, Met(O2)11]-SP only induced Ca2+ responses when applied for a long period of time and not during brief, local applications, suggesting the involvement of SP hydrolysis. Acetylcholinesterase (AChE) may not be involved in SP degradation since Ca2+ responses evoked by SP were unchanged in the presence of the cholinesterase inhibitor neostigmine. 5. Ca2+ responses induced by muscarine and nerve stimulations were almost abolished when preceded by SP applications, while those induced by ATP were significantly reduced. The rundown of the nerve-evoked Ca2+ responses in PSCs was attenuated in the presence of SR140333. 6. These results indicate that endogenous SP is involved in the regulation of PSC activity and that SP is an important modulator of glial cell Ca2+ signalling and synapse-glia communication.
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PMID:Endogenous peptidergic modulation of perisynaptic Schwann cells at the frog neuromuscular junction. 972 29

The intrathecal administration of pertussis toxin (PTX) not only blocks the antinociceptive effects of the muscarinic cholinergic receptor agonist oxotremorine administered systemically, but also produces a long-lasting thermal allodynia in mice. The purpose of the present studies was to determine both the antinociceptive effects in normal mice and the antiallodynic effects in PTX-treated mice of systemically administered muscarinic cholinergic receptor agonists and cholinesterase inhibitors. In normal mice, antinociceptive effects were tested using a 55 degrees C water-bath tail-flick test. In mice treated 7 days previously with PTX (0.3 microg i.t.), antiallodynic effects were tested using a 45 degrees C water-bath tail-flick test. The nonselective high-efficacy muscarinic agonists oxotremorine, H-TZTP (3-(1,2, 5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate), and methylthio[2.2.1], (exo (+)3-(3-methylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]heptane oxalate), as well as vedaclidine, a mixed M(2)/M(4) muscarinic receptor partial agonist and M(1)/M(3)/M(5) muscarinic receptor antagonist, the nonselective partial agonists RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tacrine all produced dose-related antinociception. Oxotremorine, H-TZTP and methylthio[2.2.1] produced dose-related reversals of PTX-induced thermal allodynia whereas vedaclidine produced a partial reversal and RS86 and pilocarpine, as well as physostigmine and tacrine, failed to reverse the allodynia. The present results provide further evidence that decrements in PTX-sensitive G(i/o)-protein functioning may be involved in initiating and/or maintaining some persistent or neuropathic pain states. Moreover, the present results suggest that muscarinic receptor agonists such as vedaclidine may be useful in the treatment of persistent pain states that are due at least in part to dysfunction of inhibitory second messenger systems.
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PMID:Reversal of pertussis toxin-induced thermal allodynia by muscarinic cholinergic agonists in mice. 1097 34

An investigation of the possible interactions between combinations of vaccines and pyridostigmine bromide (PB) has been undertaken in the guinea pig. This study is part of a research programme funded by the UK Government to determine any effects of the pretreatment regimes given to UK Forces during the Persian Gulf conflict of 1990-1991. The study was designed to simulate PB administration and to model multiple vaccination protocols that were experienced by UK Forces, modelling a "worst case" situation in which all ten vaccines and PB were administered within a short period of time. Seven of the vaccines were health and hygiene (H+H) vaccines given to protect against endemic diseases and two vaccines to protect against the biological warfare agents anthrax and plague. In addition, pertussis vaccine was administered as an adjuvant to reduce the time to achieve immunity against anthrax. Four groups of eight animals were treated with 1/20th, 1/10th or 1/5th human doses of vaccines or vehicles, respectively. The PB or saline was delivered by implanted 28 day mini-osmotic pumps to achieve a mean red blood cell acetylcholinesterase (AChE) inhibition of around 30%. Body weight, temperature, immunological response, biochemical indices and spontaneous activity were monitored for 72 days. Although immunological responses to bacterial vaccines were observed, there were no remarkable findings in the parameters measured other than minor changes in body weight (4.9% decrease at the 1/5th human dose of vaccines) and temperature increases in response to vaccination. Animals in all groups remained generally healthy and active without visible adverse signs throughout the study. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.
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PMID:Biological consequences of multiple vaccine and pyridostigmine pretreatment in the guinea pig. 1118 Feb 81

Muscarinic acetylcholine receptors (mAChRs) play an important role in regulating the release of acetylcholine (ACh) in various tissues. We used subtype-specific antibodies and a fluorescent-labelled muscarinic toxin to demonstrate that mammalian neuromuscular junction expresses mAChR subtypes M1 to M4, and that localization of all subtypes is highly restricted to the innervated part of the muscle. To elucidate the roles of the mAChR subtypes regulating ACh release, we measured the mean quantal content of endplate potentials in isolated mouse phrenic--hemidiaphragm preparations in which release was reduced by a low Ca2+/high Mg2+ medium. Muscarine decreased evoked ACh release in normal junctions but, depending on the concentration, reduced or increased transmitter release in collagen Q-deficient junctions completely lacking acetylcholinesterase (AChE). Both effects were also seen in normal junctions when AChE was inhibited by various doses of fasciculin-2. Block of mAChRs by atropine had no effect on evoked release at normal junctions, but decreased release at junctions lacking AChE. The muscarine-elicited depression of ACh release in normal junctions was completely abolished by pertussis toxin or methoctramine pretreatment, but was not affected by muscarinic toxin MT-3, thus indicating the involvement of the M2 mAChR. The muscarine-induced increase of ACh release in AChE-deficient junctions was not affected by pertussis toxin, but was completely blocked by MT-7, a specific M1 mAChR antagonist. Our results show that the M1 and M2 mAChRs have opposite presynaptic functions in modulating quantal ACh release, and that regulation of release by the two receptor subtypes depends on the functional state of AChE at the neuromuscular junction.
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PMID:Regulation of acetylcholine release by muscarinic receptors at the mouse neuromuscular junction depends on the activity of acetylcholinesterase. 1187 71

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce efficacious analgesia. However, the mechanisms of the antinociceptive actions of muscarinic agonists in the spinal cord are not fully known. Previous in vitro studies have shown that muscarinic agonists increase GABA release and reduce the glutamatergic synaptic input to lamina II interneurons through GABAB receptors in the spinal cord. In the present study, we studied the effect of muscarinic agents on dorsal horn projection neurons and the role of spinal GABAB receptors in their action. Single-unit activity of ascending dorsal horn neurons was recorded in the lumbar spinal cord of anesthetized rats. The responses of dorsal horn neurons to graded mechanical stimuli were determined before and after topical spinal application of muscarine and neostigmine. We found that topical application of 0.1-5 microM muscarine or 0.5-5 microM neostigmine significantly suppressed the evoked response of dorsal horn neurons in a concentration-dependent manner. The inhibitory effect of muscarine or neostigmine on dorsal horn neurons was completely abolished in the presence of 1 microM atropine and by intrathecal pretreatment with 1 microg pertussis toxin to inactivate inhibitory G proteins. Furthermore, the inhibitory effect of both muscarine and neostigmine on the evoked response of dorsal horn neurons was significantly attenuated in the presence of 1 microM CGP55845, a GABAB receptor antagonist. Collectively, these data suggest that muscarinic agents inhibit dorsal horn projection neurons through muscarinic receptors coupled to pertussis toxin-sensitive Gi/o proteins. The inhibitory action of muscarinic agonists on these dorsal horn neurons is mediated in part by spinal GABAB receptors.
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PMID:Activation of muscarinic receptors inhibits spinal dorsal horn projection neurons: role of GABAB receptors. 1505 Nov 53

Microinjecting the acetylcholinesterase inhibitor neostigmine into the pontine reticular formation of C57BL/6J (B6) mouse causes a rapid eye movement (REM) sleep-like state. This finding is consistent with similar studies in cat and both sets of data indicate that the REM sleep-like state is caused by increasing levels of endogenous acetylcholine (ACh). Muscarinic cholinergic receptors have been localized to the pontine reticular formation of B6 mouse but no previous studies have examined which of the five muscarinic receptor subtypes participate in cholinergic REM sleep enhancement. This study examined the hypothesis that M2 receptors in pontine reticular formation of B6 mouse contribute to the REM sleep-like state caused by pontine reticular formation administration of neostigmine. B6 mice (n=13) were implanted with electrodes for recording states of sleep and wakefulness and with microinjection cannulae aimed for the pontine reticular formation. States of sleep and wakefulness were recorded for 4 h following pontine reticular formation injection of saline (control) or neostigmine. Experiments designed to gain insight into the muscarinic receptor subtypes mediating REM sleep enhancement involved pontine reticular formation administration of neostigmine after pertussis toxin, neostigmine after methoctramine, and neostigmine after pirenzepine. Pertussis toxin was used to block effects mediated by M2 and M4 receptors. Methoctramine was used to block M2 and M4 receptors, and pirenzepine was used to block M1 and M4 receptors. Pertussis toxin and methoctramine significantly decreased the neostigmine-induced REM sleep-like state. In contrast, pretreatment with pirenzepine did not significantly decrease the REM sleep-like state caused by neostigmine. These results support the interpretation that M2 receptors in the pontine reticular formation of B6 mouse contribute to the generation of REM sleep.
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PMID:M2 muscarinic receptors in pontine reticular formation of C57BL/6J mouse contribute to rapid eye movement sleep generation. 1520 17


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