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Activation and desensitization of peripheral muscle and neuronal nicotinic acetylcholine receptors by selected, naturally-occuring pyridine alkaloids

Author:
Benedict T. Green, Stephen T. Lee, Kevin D. Welch, Daniel Cook
Source:
Toxins 2016 v.8 no.7 pp. 204
ISSN:
2072-6651
Subject:
acetylcholine, agonists, anabasine, cholinergic receptors, fetus, muscles, neurons, nicotine, teratogenicity, teratogens, toxins
Abstract:
Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement that results from desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChRs). We investigated the ability of two known teratogens, the piperidinyl-pyridine anabasine and its 1,2-dehydropiperidinyl analog anabaseine, to activate and desensitize peripheral nAChRs expressed in TE-671 and SH-SY5Y cells. Activation-concentration response curves for each alkaloid were obtained in the same multi-well plate. To measure rapid desensitization, cells were first exposed to five potentially-desensitizing concentrations of each alkaloid in log10 molar increments from 10 nM to 100 M and then to a fixed concentration of acetylcholine (ACh), which alone produces near-maximal activation. The fifty percent desensitization concentration (DC50) was calculated from the alkaloid concentration-ACh response curve. Agonist fast desensitization potency was predicted by the agonist potency measured in the initial response. Anabaseine was a more potent desensitizer than anabasine. Relative to anabaseine, nicotine was more potent to autonomic nAChRs, but less potent to the fetal neuromuscular nAChRs. Our experiments have demonstrated that anabaseine is more effective at desensitizing fetal muscle-type nAChRs than anabasine or nicotine and, thus, it is predicted to be more teratogenic.
Agid:
62924
Handle:
10113/62924