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

---

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

Several lines of evidence suggest the non-cholinergic functions of acetylcholinesterase (AChE) in promoting neurite outgrowth of cultured neurons and in inducing the postsynaptic specializations of developing neuromuscular junctions. In order to support the hypothesis, a cholinergic synapse-forming cell line NG108-15 was over-expressed with chick AChE by cDNA transfection. The transfected NG108-15 cells secreted a approximately 105-kDa protein, recognized by anti-AChE antibody in Western blot analysis, corresponding to the chick AChE catalytic subunit. Over 80% of the recombinant enzyme were secreted into the conditioned medium and they were enzymatically active. In the NG108-15 cell-muscle co-cultures, the AChR-aggregating activity of NG108-15 cells was increased by the over-expression of AChE. The increase in AChR-aggregating activity of the transfected NG108-15 cells paralleled with the increase in agrin and neurofilament expression of the transfected cells as determined by their corresponding antibodies. However, the intracellular cAMP level remained unchanged in the AChE over-expressed NG108-15 cells. These results support the hypothesis that AChE could play a role in promoting neuron differentiation.
...
PMID:Over-expression of acetylcholinesterase stimulates the expression of agrin in NG108-15 cells. 966 53

Cholinergic hybrid mouse septal neurons SN56 were differentiated by separate and combined application of 0.001 mM all-trans-retinoic acid and 1 mM dibutyryl cAMP. Each of agents caused about twofold increase of choline acetyltransferase activity. These activatory effects were additive. Dibutyryl cAMP resulted in twofold increase of ATP-citrate lyase and acetylcholinesterase activities. Retinoic acid did not affect these enzyme activities but partially abolished activatory effects of dibutyryl cAMP. Pyruvate dehydrogenase and other enzymes of acetyl-CoA metabolism were not affected by this treatment. This work demonstrates that it is possible to rise cholinergic neurons of different expression of cholinergic and acetyl-CoA metabolism.
...
PMID:Activities of enzymes of acetyl-CoA and acetylcholine metabolism in SN56 hybrid cholinergic cell line differentiated by dibutyryl cyclic AMP and all-trans retinoic acid. 983 4

The rate of acetylcholine (ACh) synthesis was found to depend on the activity of choline acetyltransferase (ChAT) and on the concentrations of the two substrates of this enzyme, choline and acetyl-CoA. In SN56 cells treated for 3 days with 1 mM dbcAMP activities of ChAT and acetylcholinesterase (AChE) were elevated. It was accompanied by an increased activity of ATP-citrate lyase (ACL)-an enzyme responsible for provision of part of acetyl-CoA for ACh synthesis in cholinergic neurons. In contrast lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities were reduced by dbcAMP. Treatment with 0.001 mM all-trans retinoic acid (RA) elevated ChAT and LDH activities but reduced the activities of AChE and ACL. The combined treatment with db-cAMP and tRA increased ChAT activity in supra-additive fashion. The effects of these two compounds on the other enzymes were not additive. Neither compound altered the activities of carnitine acetyl-transferase, acetyl-CoA synthase, or acetyl-CoA hydrolase. On the other hand, they decreased acetyl-CoA content and rate of ACh release. Overall, the results indicate that tRA upregulates only ChAT expression, whereas dbcAMP upregulates several features of cholinergic neurons including ChAT, AChE, and ACL. Low levels of acetyl-CoA in differentiated cells may result in a low rate of ACh release and resynthesis during their depolarization.
...
PMID:Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line. 1039 43

Milameline (E-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride, CI-979, PD129409, RU35926) was characterized in vitro and evaluated for effects on central and peripheral cholinergic activity in rats and rhesus monkeys. In muscarinic binding studies, milameline displayed nanomolar affinity with an agonist ligand and micromolar affinity with antagonist ligands, with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM(1)-hM(5)) with whole cells or membranes from stably transfected Chinese hamster ovary (CHO) cells. On binding, milameline stimulated phosphatidylinositol hydrolysis in hM(1) and hM(3) CHO cells and inhibited forskolin-activated cAMP accumulation in hM(2) and hM(4) CHO cells. Additionally, it decreased K(+)-stimulated release of [(3)H]acetylcholine from rat cortical slices. Responses were not caused by the inhibition of acetylcholinesterase, and there was no significant binding to approximately 30 other neurotransmitter binding sites. In rats, milameline decreased spontaneous and scopolamine-induced swimming activity, improved water-maze performance of animals impaired by basal forebrain lesions, increased cortical blood flow, decreased core body temperature, and increased gastrointestinal motility. Electroencephalogram activity in both rats and monkeys was characterized by a predominance of low-voltage desynchronized activity consistent with an increase in arousal. Milameline also reversed a scopolamine-induced impairment of attention on a continuous-performance task in monkeys. Thus, milameline possesses a pharmacological profile consistent with that of a partial muscarinic agonist, with central cholinergic actions being produced in rats and monkeys at doses slightly lower than those stimulating peripheral cholinergic receptors.
...
PMID:Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization. 1052 4

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 microM peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent Km of PKA for cAMP increased from approximately 10(-8) to 10(-6) M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.
...
PMID:Protein nitration. 1119 83

Cyclic adenosine 3',5'-monophosphate (cAMP)-dependent signalling pathway has been proposed to regulate acetylcholinesterase (AChE) expression in chick muscle; however, its role in mammalian enzyme is not known. We provide several lines of evidence to suggest that the cAMP-mediated AChE expression in myotube is oppositely regulated between avian and mammalian enzymes. Human AChE promoter was tagged with luciferase, namely Hp-Luc, which was transfected into cultured chick myotubes. Application of cAMP and forskolin induced the expression of chick AChE but reduced human AChE promoter-driven luciferase activity. Transfection of cDNAs encoding active mutants of G proteins altered the intracellular cAMP level in myotubes as well as the expression of chick and human AChE. When the constitutively active forms of Activating Transcription Factor-1 (EWS/ATF-1 oncogene) were over expressed in Hp-Luc transfected myotubes, the expression of chick AChE transcript and protein increased from approximately 1.8- to approximately 2.5-fold, but the luciferase activity was decreased by over 60%. Overexpression of cAMP-responsive element binding protein (CREB) in Hp-Luc transfected myotubes markedly enhanced the cAMP-mediated AChE expression in up- and downregulated chick and human enzymes, respectively. In addition, CREB bound the CRE sequence of human AChE promoter. Mutation on the CRE site markedly enhanced the expression of the promoter-driven luciferase; however, its response to cAMP inhibition in cultured myotubes was still retained. These findings suggest that a cAMP-dependent pathway is contrasting activation and repression of AChE expression in chick and human muscles.
...
PMID:The cyclic AMP-mediated expression of acetylcholinesterase in myotubes shows contrasting activation and repression between avian and mammalian enzymes. 1131 8

Parathion (PS) and chlorpyrifos (CPF) are organophosphorus insecticides, which elicit toxicity following biotransformation to the potent acetylcholinesterase inhibitors, paraoxon (PO) and chlorpyrifos oxon (CPO). Both oxons have also been shown to interact directly with muscarinic receptors coupled to inhibition of adenylyl cyclase. Immature animals are more sensitive than adults to the acute toxicity of PS and CPF but little is known regarding possible age-related differences in interactions between these toxicants and muscarinic receptors. We compared the inhibition of forskolin-stimulated cAMP formation by PO and CPO (1 nM-1 mM) in vitro in brain slices from 7-, 21-, and 90-day-old rats to the effects of well-known muscarinic agonists, carbachol and oxotremorine (100 microM). Both agonists inhibited cAMP formation in tissues from all age groups and both were more effective in adult and juvenile (20-26% inhibition) than in neonatal (12-13% inhibition) tissues. Atropine (10 microM) completely blocked agonist-induced inhibition in all cases. PO maximally inhibited (37-46%) cAMP formation similarly in tissues from all age groups, but atropine blocked those effects only partially and only in tissues from 7-day-old rats. CPO similarly inhibited cAMP formation across age groups (27-38%), but ATR was partially effective in tissues from all three age groups. Both oxons were markedly more potent in tissues from younger animals. We conclude that PO and CPO can directly inhibit cAMP formation through muscarinic receptor-dependent and independent mechanisms and that the developing nervous system may be more sensitive to these noncholinesterase actions.
...
PMID:Inhibition of forskolin-stimulated cAMP formation in vitro by paraoxon and chlorpyrifos oxon in cortical slices from neonatal, juvenile, and adult rats. 1183 23

Chlorpyrifos (CPF) is a widely used organophosphorus pesticide. Earlier work from our laboratory and others has demonstrated that the sensitivity to CPF exposure changes markedly during maturation. A number of studies suggest that in addition to inhibiting acetylcholinesterase (AChE), CPF oxon may also interact directly with m2 and/or m4 subtypes of muscarinic acetylcholine receptors (mAChRs). In the present study, we investigated the in vivo effects of CPF exposure on phosphoinositide (PI) hydrolysis and cAMP formation, second-messenger systems coupled to m1, m3 and m5 (PI hydrolysis) or m2 and m4 (cAMP formation) mAChRs. Neonatal (7-day), juvenile (21-day) and adult (90-day) rats were treated with either peanut oil s.c. or CPF s.c. at 0.3x or 1x the maximum tolerated dosage (MTD: 45, 127 and 279 mg/kg for 7-day, 21-day and 90-day rats, respectively). Neurochemical end-points including AChE activity, muscarinic receptor ([3H]quinuclidinyl benzilate, and [3H]oxotremorine) binding, PI hydrolysis, and cAMP formation in cortex were evaluated at 4 h, 24 h, or 96 h after treatment. Under these conditions, relatively similar maximal degrees of cholinesterase (ChE) inhibition were noted, but times to peak inhibition varied among these age groups (24 h in neonates and juveniles, 96 h in adults). Total muscarinic receptor (QNB) binding was reduced in all three age groups with 1x MTD exposure, at both 24 h and 96 h in neonates and juveniles, but only at 96 h in adults. Oxotremorine binding was also reduced at 96 h after MTD exposure in all three age groups. Neither basal nor carbachol-stimulated IP accumulation was affected in any age group or at any time point following CPF exposure. In contrast, basal cAMP formation was significantly increased by MTD exposure in all three age groups 4 h after exposure, and at 4 h, 24 h, and 96 h after exposure in juveniles. Forskolin/Mn2+-stimulated cAMP formation was increased in neonates and juveniles at 96 h, and in juveniles also at 24 h, but was significantly decreased in adults at 96 h after MTD exposure. Oxotremorine-mediated inhibition of cAMP formation was significantly greater at 96 h after MTD exposure in all three age groups. These results provide further evidence that the cortical cAMP signaling pathway may be particularly sensitive to CPF exposure in neonatal, juvenile, and adult rats, possibly due to a direct interaction between CPF (or its oxon) and mAChRs or other components of the adenylyl cyclase cascade.
...
PMID:Age-related effects of chlorpyrifos on muscarinic receptor-mediated signaling in rat cortex. 1187

SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT)(4) receptors (K(i) of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT(4(b)) and 5-HT(4(e)) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT(4) antagonist with a pK(b) of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT(4) antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT(4) agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamine-induced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT(4) receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.
...
PMID:SL65.0155, a novel 5-hydroxytryptamine(4) receptor partial agonist with potent cognition-enhancing properties. 1213 Jul 38

The expression of acetylcholinesterase (AChE) is markedly increased during myogenic differentiation of C2C12 myoblasts to myotubes; the expression is mediated by intrinsic factor(s) during muscle differentiation. In order to analyze the molecular mechanisms regulating AChE expression during myogenic differentiation, a approximately 2.2-kb human AChE promoter tagged with a luciferase reporter gene, namely pAChE-Luc, was stably transfected into C2C12 cells. The profile of promoter-driven luciferase activity during myogenic differentiation of C2C12 myotubes was found to be similar to that of endogenous expression of AChE catalytic subunit. The increase of AChE expression was reciprocally regulated by a cAMP-dependent signaling pathway. The level of intracellular cAMP, the activity of cAMP-dependent protein kinase, the phosphorylation of cAMP-responsive element binding protein and the activity of cAMP- responsive element (CRE) were down-regulated during the myotube formation. Mutating the CRE site of human AChE promoter altered the original myogenic profile of the promoter activity and its suppressive response to cAMP. In addition, the suppressive effect of the CRE site is dependent on its location on the promoter. Therefore, our results suggest that a cAMP-dependent signaling pathway serves as a suppressive element in regulating the expression of AChE during early myogenesis.
...
PMID:A cyclic AMP-dependent pathway regulates the expression of acetylcholinesterase during myogenic differentiation of C2C12 cells. 1214 Feb 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---