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 two parameters of the active [methyl-3H]choline uptake into isolated rat forebrain microvessels, Km and Vmax, were determined for 1-, 3-, 10-, and 24-month-old Charles River male rats and compared with the activities of the enzymes choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) in these microvessels over the same time course. The value of Km remained constant over the entire period, but that of Vmax increased from 8.5 +/- 1.0 to 80.6 +/- 16.4 nmol g-1 (mean +/- SEM) over the first 3 months of life. Over the same period, the increase in ChAT activity, from an initial value of 7.1 +/- 1.6 to 10.2 +/- 0.3 nmol g-1 min-1, was not proportional to that of choline uptake. Levels of BuChE activity (0.9-1.3 mumol g-1 min-1) were almost unchanged throughout the entire 24-month period, but those of AChE showed a steady and significant increase from 1 to 24 months, remaining relatively high at senescence (4.7 mumol g-1 min-1), when choline uptake had decreased to one-third of its optimal value. Selective inhibition of AChE with 1,5-bis(4-allyldimethylammonium-phenyl)pentan-3-one dibromide (0.5 microM) in unruptured capillaries from 3-month-old rats resulted in a decrease in Vmax of choline uptake from approximately 81 to 59 nmol g-1 min-1 or with 9-amino-1,2,3,4-tetrahydroacridine (10 microM) in capillaries from 2-month-old rats from approximately 30 to 15 nmol g-1 min-1. Selective inhibition of BuChE with tetraisopropyl pyrophosphoramide (100 microM) resulted in an increase in Vmax from approximately 81 to 96 nmol g-1 min-1. It is possible that the two vascular enzyme systems are coupled to a hypothetical endothelial choline transporter, but with an action opposite to each other.
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PMID:Vascular cholinesterases and choline uptake in isolated rat forebrain microvessels: a possible link. 274 36

Cholinergic neurons in PNS and CNS are identified by the presence of choline acetyltransferase and the accumulation of choline by a high-affinity, sodium-coupled choline transporter to be used for acetylcholine synthesis. It appears that expression of choline acetyltransferase can be altered by several physiological conditions, including hormones and trophic factors, but little is known about control of expression of the sodium-coupled choline carrier or whether these two phenotypic markers are regulated similarly. In the present study, the cholinergic human neuroblastoma LA-N-2 was used to investigate regulation of expression of choline acetyltransferase and choline uptake activity associated with differentiation and neurite extension. Cells grown in serum-containing basal medium maintained a relatively undifferentiated morphology, expressed low levels of choline acetyltransferase activity, and accumulated choline by a sodium-dependent process followed by conversion to acetylcholine. Transfer of cells to an enriched, serum-free defined medium resulted in morphological and neurochemical differentiation, with an enhancement of cholinergic phenotype. Hemicholinium-sensitive choline uptake activity was increased about sixfold over a 4-day period, with no change in choline acetyltransferase or acetylcholinesterase specific activity. Acetylcholine synthesis was increased in parallel with the changes in choline accumulation; choline metabolism in the differentiated cells differed significantly from that observed in the undifferentiated cells, with proportionally less converted to phosphorylcholine and proportionally more remaining as unmetabolized choline and converted to acetylcholine. The enhanced choline accumulation appeared to be mediated by an increased number of choline carriers, demonstrated by increased binding of the affinity ligand [3H]-choline mustard to the transporter and by an increased Vmax for the uptake process. The increased expression of the transport function appeared to be under transcriptional control, as the enhancement of uptake was blocked by the RNA polymerase II inhibitor alpha-amanitin as well as by the protein synthesis inhibitor cycloheximide. These results show that expression of sodium-coupled choline carriers and choline acetyltransferase may be regulated separately in the differentiating neuroblastoma LA-N-2 and that neurotransmitter synthesis is controlled by provision of precursor rather than at the level of the biosynthetic enzyme.
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PMID:Regulation of expression of cholinergic neuronal phenotypic markers in neuroblastoma LA-N-2. 837 93

High, subcutaneous doses of the organophosphorus insecticide chlorpyrifos (CPF) in adult male rats can be well-tolerated despite extensive and persistent acetylcholinesterase (AChE) inhibition. We propose that changes in acetylcholine synthesis could modulate the toxicity associated with extensive AChE inhibition following CPF exposure. High-affinity choline uptake (HACU, the rate-limiting step in acetlcholine synthesis) and binding to [3H]-hemicholinium-3 (HC-3, a specific ligand for the choline transporter) were chosen as indicators of acetylcholine synthesis. Female, Sprague-Dawley rats (220-280 g) were treated with either vehicle (peanut oil, 2 ml/kg, sc) or CPF (280 mg/kg, 2 ml/kg, sc), examined daily for clinical signs of toxicity, and sacrificed 1, 2, or 7 days later for neurochemical measurements (AChE inhibition, muscarinic receptor binding using [3H]quinuclidinyl benzilate (QNB) and [3H]cis-methyldioxolane (CD) as ligands, HACU and [3H]HC-3 binding) in frontal cortex. Despite extensive AChE inhibition (90-93%) at all time points, relatively minor degrees of overt toxicity were noted in CPF-treated rats. Binding to the non-selective muscarinic antagonist [3H]QNB was reduced (10-34%), whereas binding to the putative m2-selective agonist [3H]CD was increased (15-23%) at all three time points. HACU was reduced (20%) in crude synaptosomes prepared from CPF-treated rats 1 day following exposure but no significant changes were noted at 2 or 7 days after treatment. CPF-oxon, the active oxidative metabolite of CPF, was a weak inhibitor of HACU in vitro (IC50 > 200 microM). Binding to [3H]HC-3 was reduced in a dose-related manner 1 day after CPF exposure. Kinetic analyses of [3H]HC-3 binding 1 day after CPF (280 mg/kg) indicated a significant reduction in density (Bmax: control, 187 +/- 18 fmol/mg protein; CPF, 104 +/- 12 fmol/mg protein) with no apparent change in binding affinity (Kd: control, 25 +/- 3 nM; CPF, 19 +/- 3 nM). These results suggest that a reduction in HACU/acetylcholine synthesis may contribute, along with compensatory changes in cholinergic receptors, to the diminished toxicity following extensive AChE inhibition by CPF.
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PMID:Effects of chlorpyrifos on high-affinity choline uptake and [3H]hemicholinium-3 binding in rat brain. 893 95

The varepsilon4 allele of the apolipoprotein E gene constitutes the major genetic risk factor to develop Alzheimer's disease. If and how this protein contributes to the pathological cascade of Alzheimer's disease is not known. The varepsilon4 allele particularly affects the cholinergic defect, which is one of the most consistent neurotransmitter problems in an Alzheimer's disease brain. We have analysed several parameters of the cholinergic system in brain of apolipoprotein E knockout mice as well as in transgenic mice overexpressing human apolipoprotein E4. We analysed the distribution of cholinergic fibers, the number and morphology of cholinergic neurons and the enzymatic activity of acetylcholinesterase and choline acetyltransferase in different brain regions. Finally, we analysed the distribution and the binding parameters of [3H]hemicholinium-3, a specific marker for the high affinity choline transporter in different brain sections and regions. This extensive effort failed to show any consistent difference in the cholinergic parameters studied, in either the apolipoprotein E4 transgenic mice or in the apolipoprotein E knockout mice, compared to age-matched non-transgenic mice. We conclude that the apolipoprotein E4 is not deleterious per se for the cholinergic system in mouse brain.
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PMID:No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice. 1082 23

Presynaptic synthesis of acetylcholine (ACh) requires a steady supply of choline, acquired by a plasma membrane, hemicholinium-3-sensitive (HC-3) choline transporter (CHT). A significant fraction of synaptic choline is recovered from ACh hydrolyzed by acetylcholinesterase (AChE) after vesicular release. Although antecedent neuronal activity is known to dictate presynaptic CHT activity, the mechanisms supporting this regulation are unknown. We observe an exclusive localization of CHT to cholinergic neurons and demonstrate that the majority of CHTs reside on small vesicles within cholinergic presynaptic terminals in the rat and mouse brain. Furthermore, immunoisolation of presynaptic vesicles with multiple antibodies reveals that CHT-positive vesicles carry the vesicular acetylcholine transporter (VAChT) and synaptic vesicle markers such as synaptophysin and Rab3A and also contain acetylcholine. Depolarization of synaptosomes evokes a Ca2+-dependent botulinum neurotoxin C-sensitive increase in the Vmax for HC-3-sensitive choline uptake that is accompanied by an increase in the density of CHTs in the synaptic plasma membrane. Our study leads to the novel hypothesis that CHTs reside on a subpopulation of synaptic vesicles in cholinergic terminals that can transit to the plasma membrane in response to neuronal activity to couple levels of choline re-uptake to the rate of ACh release.
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PMID:Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. 1458 97

Cholinesterase inhibitors are commonly used to improve cognition and treat psychosis and other behavioral symptoms in Alzheimer's disease, Parkinson's disease, and other neuropsychiatric conditions. However, mechanisms may exist that down-regulate the synaptic response to altered cholinergic transmission, thus limiting the efficacy of cholinomimetics in treating disease. Acetylcholinesterase knockout (AChE-/-) mice were used to investigate the neuronal adaptations to diminished synaptic acetylcholine (ACh) metabolism. The striatum of AChE-/- mice showed no changes in choline acetyltransferase activity or levels of the vesicular ACh transporter but showed striking 60% increases in the levels of the highaffinity choline transporter. This transporter takes choline from the synapse into the neuron for resynthesis of ACh. In addition, the striata of AChE-/- mice showed dramatic reductions in levels of the M1, M2, and M4 muscarinic ACh receptors (mAChRs), but no alterations in dopamine receptors or the beta2 subunit of nicotinic receptors. M1, M2, and M4 also showed decreased dendritic and cell surface distributions and enhanced intracellular localizations in striatal neurons of AChE-/- mice. mAChR antagonist treatment reversed the shifts in mAChR distribution, indicating that internalized receptors in AChE-/- mice can recover to basal distributions. Finally, AChE-/- mice showed increased sensitivity to mAChR antagonist-induced increases in locomotor activity, demonstrating functional mAChR down-regulation. mAChR downregulation in AChE-/- mice has important implications for the long-term use of cholinesterase inhibitors and other cholinomimetics in treating disorders characterized by perturbed cholinergic function.
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PMID:Altered striatal function and muscarinic cholinergic receptors in acetylcholinesterase knockout mice. 1464 60

Lymphocytes express most of the cholinergic components found in the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase. Stimulation of T and B cells with ACh or another mAChR agonist elicits intracellular Ca2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and IL-2-induced signal transduction, probably via M3 and M5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca2+ signaling in T and B cells, probably via alpha7 nAChR subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Activation of T cells with phytohemagglutinin or antibodies against cell surface molecules enhances lymphocytic cholinergic transmission by activating expression of ChAT and M5 mAChR, which is suggestive of local cholinergic regulation of immune system activity. This idea is supported by the facts that lymphocytic cholinergic activity reflects well the changes in immune system function seen in animal models of immune deficiency and immune acceleration. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.
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PMID:The lymphocytic cholinergic system and its contribution to the regulation of immune activity. 1465 62

Acetylcholine (ACh) is classically thought of as a neurotransmitter in mammalian species. However, lymphocytes express most of the cholinergic components found in the nervous system, including ACh, choline acetyltransferase (ChAT), high-affinity choline transporter, and acetylcholinesterase as well as both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Activation of T cells via the T cell receptor/CD3 complex, contact of T cells with antigen presenting cells, or activation of the adenylyl cyclase pathway in T cells modulates cholinergic activity, as evidenced by up-regulation of ChAT and M(5) mAChR mRNA expression. Stimulation of mAChRs on T and B cells with ACh or another mAChR agonists elicits intracellular Ca(2+) signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and interleukin-2-induced signal transduction via M(3) and M(5) mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca(2+) signaling in T and B cells, probably via alpha7 nAChRs subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Abnormalities in lymphocytic cholinergic system have been seen in animal models of immune deficiency and immune acceleration. Collectively, these data provided a compelling picture in which immune function is, at least partly, under the control of an independent, non-neuronal cholinergic system in lymphocytes.
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PMID:[An independent, non-neuronal cholinergic system in lymphocytes and its roles in regulation of immune function]. 1499 30

Lymphocytes express most components of the cholinergic system including acetylcholine (ACh), muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), choline acetyltransferase (ChAT), high affinity choline transporter and acetylcholinesterase. ACh and mAChR agonists elicit intracellular Ca2+ signaling, up-regulation of c-fos expression and nitric oxide synthesis within T and B cells probably via M3 and M5 mAChRs. Stimulation of nAChRs with ACh or nicotine causes a rapid and transient Ca2+ signaling in T and B cells, probably via alpha7 nAChR subunit-mediated pathways. Phytohemagglutinin- or antigen-induced T cell activation via cell surface molecules (e.g., T cell receptor/CD3 complexes) enhances lymphocytic cholinergic transmission by up-regulating ChAT and M5 mAChR expression. It is thus likely that a local lymphocytic cholinergic system is involved in regulating immune function. This idea is supported by the findings that lymphocytic cholinergic activity is altered in animal models exhibiting immunological abnormalities. In addition, it appears likely that during interactions mediated by cell surface molecules T cells communicate via ACh with thymic epithelial cells and vascular endothelial cells, which also express ChAT and nAChRs or mAChRs. This interaction leads to T cell selection and maturation in the thymus and local vascular smooth muscle relaxation. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function and local circulation.
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PMID:Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. 1535 71

The neurochemical effects of repeated postnatal exposure to chlorpyrifos (CPS) were studied in developing rats. Rats were gavaged daily from postnatal day (PND) 1-21 with CPS in corn oil starting at 1.5 mg/kg (low dosage group) and increasing gradually to 3 mg/kg and then to 6 mg/kg (high dosage group). Brain cholinesterase (ChE) activity was significantly inhibited on PND 6, 12, 22, and 30, with maximum inhibition on PND 6 of 49 and 59% and recovering to 18 and 33% on PND 30 in the low and high dosage groups, respectively. On PND 22 and 30, 94% or greater of the inhibited ChE could not be reactivated by the oxime TMB-4 in both treatment groups, indicating aging of the phosphorylated ChE. Total muscarinic acetylcholine receptors (mAChR) were reduced in a dose-related manner on PND 12 and 22, with substantial recovery by PND 30. M1/M3 mAChR were significantly reduced on PND 6 and 12 only in the high dosage group, and on PND 22 in both groups, while M2/M4 mAChR were reduced in the high dosage group on PND 22 and 30. On PND 30 choline acetyltransferase activity and vesicular acetylcholine transporter levels were decreased by 12 and 22%, respectively, only in the high dosage group. High-affinity choline transporter levels were decreased at all time points in the high dosage group and on PND 6, 22, and 30 in the low dosage group. The results presented here demonstrate that repeated postnatal exposures to CPS result in transient reductions of mAChR and more persistent alterations of presynaptic cholinergic neurons. In addition, the long-term reduction of brain ChE activity observed following repeated postnatal exposure to CPS is attributable to permanent inactivation or "aging" of the enzyme.
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PMID:Effects of repeated oral postnatal exposure to chlorpyrifos on cholinergic neurochemistry in developing rats. 1564


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