Direct actions of anticholinesterases on the neuronal nicotinic acetylcholine receptor channels

Nagata, Keiichi; Huang, Chien-Sheng; Song, Jin-Ho; Narahashi, Toshio

doi:10.1016/s0006-8993(97)00707-5

Cited by 49 publications

(44 citation statements)

References 17 publications

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“…Among the ACh receptor families, the effects of nAChRs were much more widespread than for mAChRs, possibly a reflection of the ability of organophosphates to interact directly with these receptors and block their function [42,68,98]. This is particularly important during brain development, where the various nAChR subtypes have specific roles in neurotrophic responses, differentiation, damage/repair, neuritic outgrowth and organophosphate neurotoxicity [7,44,95,111].…”

Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 99%

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

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Organophosphates affect mammalian brain development through a variety of mechanisms beyond their shared property of cholinesterase inhibition. We used microarrays to characterize similarities and differences in transcriptional responses to chlorpyrifos and diazinon, assessing defined gene groupings for the pathways known to be associated with the mechanisms and/or outcomes of chlorpyrifos-induced developmental neurotoxicity. We exposed neonatal rats to daily doses of chlorpyrifos (1 mg/kg) or diazinon (1 or 2 mg/kg) on postnatal days 1-4 and evaluated gene expression profiles in brainstem and forebrain on day 5; these doses produce little or no cholinesterase inhibition. We evaluated pathways for general neural cell development, cell signaling, cytotoxicity and neurotransmitter systems, and identified significant differences for >60% of 252 genes. Chlorpyrifos elicited major transcriptional changes in genes involved in neural cell growth, development of glia and myelin, transcriptional factors involved in neural cell differentiation, cAMP-related cell signaling, apoptosis, oxidative stress, excitotoxicity, and development of neurotransmitter synthesis, storage and receptors for acetylcholine, serotonin, norepinephrine and dopamine. Diazinon had similar effects on many of the same processes but also showed major differences from chlorpyrifos. Our results buttress the idea that different organophosphates target multiple pathways involved in neural cell development but also that they deviate in key aspects that may contribute to disparate neurodevelopmental outcomes. Equally important, these pathways are compromised at exposures that are unrelated to biologically significant cholinesterase inhibition and its associated signs of systemic toxicity. The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity.

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Section: Cpf and Dzn Effects On Neurotransmitter Systemsmentioning

confidence: 99%

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Slotkin

Seidler

2007

Brain Research Bulletin

193

208

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“…The muscarinic receptor antagonist atropine causes mixed coagonist and antagonist effects on rat neuronal nicotinic receptors (Zwart and Vijverberg, 1997). Effects resembling those of d-tubocurarine and atropine on rat nicotinic acetylcholine receptors have been described for several acetylcholinesterase inhibitors, e.g., for galanthamine (Schrattenholz et al, 1996;Samochocki et al, 2003), neostigmine (Nagata et al, 1997), and physostigmine (Zwart et al, 2000). Despite the similar coagonist and antagonist effects of these diverse cholinergic drugs on nicotinic acetylcholine receptors, the mechanism of potentiation has not been agreed upon yet, not in the least because of the large variability in potentiation and inhibition reported and in the nicotinic acetylcholine receptor subtypes involved.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic drugs potentiate human nicotinic α4β2 acetylcholine receptors by a competitive mechanism

Smulders

Zwart

Bermúdez

et al. 2005

European Journal of Pharmacology

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Effects of cholinergic drugs on human a4h2 nicotinic acetylcholine receptors expressed in Xenopus oocytes have been investigated in electrophysiological and ligand binding experiments. Atropine, scopolamine, physostigmine, and tacrine combine potentiation of ion current induced by low concentrations of acetylcholine with inhibition of ion current evoked by high concentrations of acetylcholine. Rivastigmine, galanthamine, and dichlorvos cause only inhibition of ion current evoked by low concentrations of acetylcholine. Binding experiments show that the potentiating cholinergic drugs atropine, scopolamine, and physostigmine are competitive ligands of human a4h2 nicotinic acetylcholine receptors. Conversely, the inhibitory cholinergic drugs galanthamine and rivastigmine are non-competitive. The noncompetitive drugs are not allosteric, since they do not affect the saturation curve of the radioligand [ 3 H]cytisine. Effects of potentiating cholinergic drugs on nicotinic acetylcholine receptors are consistent with and predicted by a model comprising competitive drug effects at two equivalent agonist recognition sites on the nicotinic acetylcholine receptor combined with non-competitive ion channel block. D

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“…Agonistic, antagonistic, potentiating, and inhibitory effects of physostigmine and related cholinesterase inhibitors on nicotinic ACh receptors (nAChRs) have also been described. Low concentrations of physostigmine and neostigmine agonize or potentiate, whereas high concentrations of these drugs block neuronal nAChR channels (Storch et al, 1995;Nagata et al, 1997;Van den Beukel et al, 1998). High concentrations of physostigmine also block the ion channel of muscle-type nAChRs (Wachtel, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…Like neostigmine, carbaryl causes a concentration-dependent potentiation and inhibition of neuronal nAChR channels in rat pheochromocytoma PC12 cells (Nagata et al, 1997). An observed enhancement of cholinergic transmission in guinea pig myenteric plexus preparations has been proposed to be associated with an effect of the dithiocarbamate fungicide propineb on ganglionic and not on muscle-type nAChRs (Marinovich et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

Smulders

Bueters²,

Kleef

et al. 2003

Toxicology and Applied Pharmacology

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Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit ␣4␤4 nicotinic receptors is fenoxycarb Ͼ EPTC Ͼ carbaryl, bendiocarb Ͼ propoxur Ͼ aldicarb with IC50 values ranging from 3 M for fenoxycarb to 165 M for propoxur and Ͼ1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb Ͼ propoxur, aldicarb Ͼ carbaryl Ͼ Ͼ EPTC, fenoxycarb with IC50 values ranging from 1 M for bendiocarb to 17 M for carbaryl and Ͼ Ͼ1 mM for EPTC and fenoxycarb. The ␣4␤2, ␣3␤4, and ␣3␤2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for ␣4␤4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the ␣3␤2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of ␣ and ␤ subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure.

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Direct actions of anticholinesterases on the neuronal nicotinic acetylcholine receptor channels

Cited by 49 publications

References 17 publications

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

Cholinergic drugs potentiate human nicotinic α4β2 acetylcholine receptors by a competitive mechanism

Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase

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