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)

Cat superior cervical ganglia (SCG), denervated preganglionically 6-8 d previously, were stained for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by the bis-(thioacetoxy)aurate (I), or Au(TA)2, method and compared by electron microscopy with normal SCG described previously (Davis, R., and G. B. Koelle. 1978. J. Cell Biol. 78:785-809). In confirmation of earlier light microscopic findings by the highly specific copper thiocholine method, there was nearly a total disappearance of AChE from the ganglion; no myelinated or unmyelinated axons with AChE-stained axolemmas were found, and only occasional traces of AChE staining were noted at dendritic and perikaryonal plasma membranes. Considerable staining for BuChE persisted at the latter sites, however. As in the normal SCG, physostigmine-resistant staining, caused by noncholinesterase enzymes plus the possible presence of very low concentrations of AChE or BuChE, was noted at external mitochondrial membranes, elements of the endoplasmic reticulum of neurites and Schwann cells, and also in lysosomes. These findings confirm the previous identification of AChE-stained myelinated fibers in the normal SCG as preganglionic and of the unstained myelinated fibers as postganglionic. It is proposed that the maintenance of AChE at postsynaptic sites in normal ganglia is caused by the release of a trophic factor(s) from presynaptic terminals. The source of the postsynaptic BuChE, which is apparently completely absent from the endoplasmic reticulum of the ganglion cells, remains unexplained.
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PMID:Electron microscope localization of acetylcholinesterase and butyrylcholinesterase in the superior cervical ganglion of the cat. II. Preganglionically denervated ganglion. 721 5

Toxicities of pesticidal mixtures in biological systems have not been explored adequately. Therefore, mixtures of ten widely used pesticides were evaluated for their toxicity in ICR male mice (21-24 g). Mice were given four mixtures of alachlor, aldrin, atrazine, 2,4-dichlorophenoxyacetic acid, DDT, dieldrin, endosulfan, lindane, parathion and toxaphene, at 0.01, 0.1, 1.0 and 10 ppm of each of these pesticides, in drinking water for 90 days ad libitum. Also, two mixtures at 2.5 and 5 mg kg-1 of each pesticide in 7.5% Tween-80 in water were administered to additional groups of mice by oral intubation daily for up to 14 days. In relation to the control, the 90-day exposure caused a dose-dependent increase in the liver/body weight ratio (3-44%), a decrease in the pentobarbital (60 mg kg-1, i.p.)-induced sleep time (11-79%) and an increase in the metabolism of aniline (233-399%), amidopyrine (79-231%), phenacetin (127-318%) and benzo[a]pyrene (286-1633%) in the 9000 g hepatic supernatants from the mixture-treated mice. Proliferation, dilatation and fragmentation of the endoplasmic reticulum and scattering of ribosomes were noticed with mixture livers. In the 5 mg kg-1 group, 90% of the animals died by Day 8; incidence of death was considerably less in the 2.5 mg kg-1 group. The serum cholinesterase activity was inhibited by ca. 50% in the 2.5 and 5 mg kg-1 groups on either one or both of Days 8 and 15; the liver/body weight ratio increased by 24-79% and the pentobarbital-induced sleep time decreased by 80-96%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Toxicological evaluation of mixtures of ten widely used pesticides. 832 87

During the development of somites in mouse embryos, widespread activity of unspecific cholinesterase (BuChE) was demonstrated after prolonged incubation. Independent of their position, all somite cells and their derivatives (dermatome, myotome and sclerotome) exhibited enzyme activity in the perinuclear space and in the endoplasmic reticulum. The plasmalemma did not show any enzyme activity. Differentiation of the sclerotome into vertebrae was accompanied by a reduction of BuChE. However, a low enzyme reaction was still present in the first typical differentiated chondroblasts. Notochordal cells were detectable by their high BuChE content. This was also found in cells already showed severe degeneration. In addition to BuChE, acetylcholinesterase (AChE) was first visible of day 9 of embryonic development in newly formed myotubes of the myotomes. Some hypotheses on the functional significance of of embryonic BuChE are discussed in the light of these results.
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PMID:Activity of acetylcholinesterase and unspecific cholinesterase during differentiation of somites in mouse embryos. 865 10

Tacrine (tetrahydroaminoacridine) is a reversible cholinesterase inhibitor used for the treatment of Alzheimer's disease. This drug causes an elevation of serum aminotransferases in a limited population of patients. Several in vivo studies failed to elucidate the mechanism for the enzyme elevation but previous in vitro studies have indicated defects in mitochondrial function. In this study, electron microscopic, histochemical, and confocal microscopy techniques were used with primary hepatocyte cultures from humans and rats to examine the sequence of early cellular changes after tacrine exposure. Changes included ribosome alterations as early as 1-2 h following tacrine exposure at concentrations ranging between 0.1 and 1.0 mM. Mitochondrial membrane potential was also altered as indicated by decreased rhodamine 123 uptake with time. Cellular lysosome content increased as indicated by increased staining of fluorescein isothiocyanate (FITC)-conjugated dextran. The results of acid phosphatase histochemistry correlated with the FITC-dextran findings. Additionally, tacrine-related degranulation and vesiculation of the endoplasmic reticulum paralleled the ribosomal and mitochondrial changes. These subcellular changes were reproducible in rat and human hepatocytes, showing for the first time that human hepatocytes can be altered by tacrine. The molecular mechanism of the organelle changes is unknown at this time. Also, the relationship between these subcellular changes in isolated hepatocytes and the transaminase elevation noted in human populations treated with tacrine needs to be clarified.
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PMID:Functional and subcellular organelle changes in isolated rat and human hepatocytes induced by tetrahydroaminoacridine. 952 Jan 38

Acridines are nucleic acid intercalating compounds with properties relating to the complexity of their structure. Tetrahydroaminoacridine (tacrine, Cognex), a simple acridine, is a reversible inhibitor of cholinesterase activity available for the symptomatic treatment of Alzheimer's disease. Tacrine therapy causes sporadic elevations of aminotransferases in humans, and tacrine alters protein synthesis and ribosomal structure under short-term in vitro exposures in isolated hepatocytes from humans and other species. There is no clear relationship between transaminase elevation and liver damage in humans, and prolonged drug exposure to animals does not result in hepatic insult. Subcellular alterations have been described in isolated human and rodent hepatocytes, including degranulation and vesiculation of the endoplasmic reticulum (ER), aggregation of electron-dense structures within the ER, altered nuclei and nucleoli and detrimental structural and functional effects to mitochondria. Whether these changes in hepatocyte morphology and function are unique to tacrine or not is unknown, as human hepatocytes exposed to more complex acridines have not been characterized. In this study, we extended the results of in vitro studies with tacrine to acridine orange, 9-aminoacridine, quinacrine and proflavin. In primary human hepatocytes, these compounds caused a similar reduction of mitochondrial membrane potential with parallel ultrastructural changes. The 1-hydroxy and 7-hydroxy tacrine metabolites, acridine hydrochloride and acridine 9-carboxylic acid, and the non-acridine cholinesterase inhibitor eserine, did not induce characteristic subcellular ER changes but damaged mitochondria structure, reduced mitochondrial membrane potential and were cytotoxic. These data indicate that the tacrine-like subcellular changes in hepatocytes are reproducible with other acridines and cause mitochondrial dysfunction in human hepatocytes.
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PMID:Acridine-induced subcellular and functional changes in isolated human hepatocytes in vitro. 998 75

Secretion of thyroglobulin (Tg, a large homodimeric glycoprotein) is essential to deliver Tg to its site of iodination for thyroxine biosynthesis. An L2263P missense mutation in Tg has been proposed as the molecular defect causing congenital goitrous hypothyroidism in cog/cog mice due to perturbed Tg homodimerization, resulting in its retention within the endoplasmic reticulum. The mutation falls within a carboxyl-terminal region of Tg with high structural similarity to the entirety of acetylcholinesterase (AChE), a secretory protein that also forms homodimers. We provide new evidence that authentic AChE and the cholinesterase-like domain of Tg share a common tertiary structure. Moreover, we find that a Tg truncation, deleted of the cholinesterase-like region (but not a comparably sized deletion of internal Tg regions), blocks Tg export. Appending to this truncation a cDNA encoding authentic AChE results in translation of a chimeric protein in which AChE is present in a native, enzymatically active (albeit latent) conformation, and this fully rescues Tg secretion. Introduction of the cog mutation inhibits AChE enzyme activity, and established denaturing mutations of AChE block secretion of the Tg. Additional studies show that the native structure of the AChE region functions as a "dimerization domain," facilitating intracellular transport of Tg to the site of thyroid hormonogenesis.
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PMID:The acetylcholinesterase homology region is essential for normal conformational maturation and secretion of thyroglobulin. 1476 82

A mutation linked to autistic spectrum disorders encodes an Arg to Cys replacement in the C-terminal portion of the extracellular domain of neuroligin-3. The solvent-exposed Cys causes virtually complete retention of the protein in the endoplasmic reticulum when the protein is expressed in transfected cells. An identical Cys substitution was reported for butyrylcholinesterase through genotyping patients with post-succinylcholine apnea. Neuroligin, butyrylcholinesterase, and acetylcholinesterase are members of the alpha,beta-hydrolase fold family of proteins sharing sequence similarity and common tertiary structures. Although these proteins have distinct oligomeric assemblies and cellular dispositions, homologous Arg residues in neuroligin-3 (Arg-451), in butyrylcholinesterase (Arg-386), and in acetylcholinesterase (Arg-395) are conserved in all studied mammalian species. To examine whether an homologous Arg to Cys mutation affects related proteins similarly despite their differing capacities to oligomerize, we inserted homologous mutations in the acetylcholinesterase and butyrylcholinesterase cDNAs. Using confocal fluorescence microscopy and analysis of oligosaccharide processing, we find that the homologous Arg to Cys mutation also results in endoplasmic reticulum retention of the two cholinesterases. Small quantities of mutated acetylcholinesterase exported from the cell retain activity but show a greater K(m), a much smaller k(cat), and altered substrate inhibition. The nascent proteins associate with chaperones during processing, but the mutation presumably restricts processing through the endoplasmic reticulum and Golgi apparatus, because of local protein misfolding and inability to oligomerize. The mutation may alter the capacity of these proteins to dissociate from their chaperone prior to oligomerization and processing for export.
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PMID:A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. 1643 5

Autism encompasses a wide spectrum of disorders arising during brain development. Recent studies reported that sequence polymorphisms in neuroligin-3 (NLGN3) and neuroligin-4 (NLGN4) genes have been linked to autism spectrum disorders indicating neuroligin genes as candidate targets in brain disorders. We have characterized a single mutation found in two affected brothers that substituted Arg451 to Cys in NL3. Our data show that the exposed Cys causes retention of the protein in the endoplasmic reticulum (ER) when expressed in HEK-293 cells. To examine whether the introduction of a Cys in the C-terminal region of other alpha/beta-hydrolase fold proteins could promote the same cellular phenotype, we made homologous mutations in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and found a similar processing deficiency and intracellular retention (De Jaco et al., J Biol Chem. 2006, 281:9667-76). NL3, AChE and BChE mutant proteins are recognized as misfolded in the ER, and degraded via the proteasome pathway. A 2D electrophoresis coupled with mass spectrometry based approach was used to analyze proteins co-immunoprecipitating with NL3 and show differential expression of factors interacting with wild type and mutant NL3. We identified several proteins belonging to distinct ER resident chaperones families, including calnexin, responsible for playing a role in the folding steps of the AChE and NLs.
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PMID:Trafficking of cholinesterases and neuroligins mutant proteins. An association with autism. 1855 79

The SM protein UNC-18 has been proposed to regulate several aspects of secretion, including synaptic vesicle docking, priming, and fusion. Here, we show that UNC-18 has a chaperone function in neurons, promoting anterograde transport of the plasma membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein Syntaxin-1. In unc-18 mutants, UNC-64 (Caenorhabditis elegans Syntaxin-1) accumulates in neuronal cell bodies. Colocalization studies and analysis of carbohydrate modifications both suggest that this accumulation occurs in the endoplasmic reticulum. This trafficking defect is specific for UNC-64 Syntaxin-1, because 14 other SNARE proteins and two active zone markers were unaffected. UNC-18 binds to Syntaxin through at least two mechanisms: binding to closed Syntaxin, or to the N terminus of Syntaxin. It is unclear which of these binding modes mediates UNC-18 function in neurons. The chaperone function of UNC-18 was eliminated in double mutants predicted to disrupt both modes of Syntaxin binding, but it was unaffected in single mutants. By contrast, mutations predicted to disrupt UNC-18 binding to the N terminus of Syntaxin caused significant defects in locomotion behavior and responsiveness to cholinesterase inhibitors. Collectively, these results demonstrate the UNC-18 acts as a molecular chaperone for Syntaxin transport in neurons and that the two modes of UNC-18 binding to Syntaxin are involved in different aspects of UNC-18 function.
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PMID:UNC-18 promotes both the anterograde trafficking and synaptic function of syntaxin. 1859 36

The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted alpha-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.
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PMID:The cholinesterase-like domain, essential in thyroglobulin trafficking for thyroid hormone synthesis, is required for protein dimerization. 1927 74


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