Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The resting efflux of choline into the perfusate (Tyrode's solution) of isolated hearts was equal to the rate, at which choline was liberated from phospholipid degradation (Lindmar et al. 1986). Infusion of isoprenaline (2 X 10(-7) mol/l), forskolin (1-3 X 10(-6) mol/l) or 3-isobutyl-1-methylxanthine (IBMX; 3 X 10(-4) mol/l) for 40 min markedly enhanced the efflux of choline. The increase was linear during the experimental period and, in the case of isoprenaline, was blocked by 3 X 10(-7) mol/l atenolol. In the guinea-pig heart, IBMX at a threshold concentration of 10(-4) mol/l shifted the concentration-response curve for the effect of forskolin on the efflux of choline to the left by one log unit. Forskolin (10(-6) mol/l) increased also the tissue content of cyclic AMP. This effect and the increase of choline efflux evoked by forskolin were blocked by 2 X 10(-7) mol/l carbachol. Likewise, inhibition of cholinesterase activity caused by diisopropylfluorophosphate antagonized the forskolin-evoked acceleration of choline efflux indicating a response to endogenous acetylcholine. The muscarinic inhibition of the enhanced choline efflux was reversed by 3 X 10(-7) mol/l atropine. The phospholipase A2 inhibitor mepacrine as well as infusion of a low Ca2+-Tyrode's solution (0.2 instead of 1.8 mmol/l) blocked the effect of forskolin on choline efflux, whereas the generation of cyclic AMP by forskolin was unaffected by low Ca2+-solution.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The release of choline from phospholipids mediated by beta-adrenoceptor activation in isolated hearts. 243 3

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.
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PMID:Age-related effects of chlorpyrifos on muscarinic receptor-mediated signaling in rat cortex. 1187

Receptor binding assays and in vitro macroautoradiography were used to analyze muscarinic cholinergic receptors (MCR) in the cerebral frontal cortex of Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), and age-matched control brains at autopsy. Total MCR binding, detected by [(3)H]quiniclinidyl benzilate binding, did not differ significantly between the 3 groups. The concentrations of M1 subtype (M1-R), detected by [(3)H]pirenzepine binding, and high affinity state MCRs, however, were significantly lower in AD than in control and SDAT frontal cortices. No differences were detected in the affinity of these receptors for their ligands. The MCRs in AD frontal cortex were more sensitive to the agonist carbachol than were control MCRs. Autoradiography revealed a complete destruction of the laminar distribution of MCR and M1-R in AD and SDAT frontal cortices. Forskolin and phorbol ester binding sites, used to analyze second messenger systems, were significantly and markedly reduced in AD frontal cortex. In addition, coupling between MCR and second messenger systems was supersensitive in AD frontal cortex. Our findings that there are alterations in the structural distribution of MCR as well as reductions and abnormalities in second messenger systems in AD cerebral frontal cortex, suggest that drug therapy with acetylcholine precursors, choline esterase inhibitors and muscarinic agonists cannot eliminate symptoms in dementia patients. Furthermore, they point out the need for techniques to diagnose the disease prior to disintegration of the neuronal network, and the need for therapies to delay or prevent the progression of structural changes.
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PMID:Abnormalities in muscarinic cholinergic receptors and their G-protein coupling systems in the cerebral frontal cortex in Alzheimer's disease. 1537 21

The ubiquitous cholinesterase (ChE) enzymes, functioning in the termination of acetylcholine mediated neural transmission, are also reported to have additional functions. Through application of siRNAs against butyrylcholinesterase (BChE) in R28 cells, a retinal cell line with pluripotent properties, a counter-regulation between ChEs was revealed. BChE knock down resulted in an up-regulation of not only acetylcholinesterase (AChE), but also altered the signaling status of PKC and ERK. Knockdown of BChE modified ERK signaling most notably through ERK1/2 proteins, together with the transcription activator P90RSK1 and c-fos. Stimulation of the R28 cell line by forskolin revealed that ChEs are involved in an intricate cross talk between different signaling pathways. Forskolin-stimulated R28 cells displayed a robust cholinergic response, as detected by both electrophysiology and ChE expression, and changed the activation status of PKC/ERK signaling pathways. The findings in R28 cells show that ChE expressions are inversely co-regulated and act through the transcription factors c-fos and P90RSK1. Since R28 cells have the capacity to differentiate into different cell types through stimulation of signaling pathways, ChEs are likely to be associated with cell fate determination, rather than just terminating cholinergic responses.
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PMID:Counter-regulation of cholinesterases: differential activation of PKC and ERK signaling in retinal cells through BChE knockdown. 2109 73