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Toxins 2016, 8(7), 204; doi:10.3390/toxins8070204

Activation and Desensitization of Peripheral Muscle and Neuronal Nicotinic Acetylcholine Receptors by Selected, Naturally-Occurring Pyridine Alkaloids

1
Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N., Logan, UT 84341, USA
2
Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1200 Newell Road, Gainesville, FL 32610-0267, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Peter S. Spencer
Received: 29 January 2016 / Revised: 24 June 2016 / Accepted: 24 June 2016 / Published: 4 July 2016
(This article belongs to the Collection Toxicity of Natural Alkaloids)
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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 µM 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. View Full-Text
Keywords: anabaseine; anabasine; epibatidine; nicotinic acetylcholine receptor; nicotine; pyridine alkaloid anabaseine; anabasine; epibatidine; nicotinic acetylcholine receptor; nicotine; pyridine alkaloid
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Green, B.T.; Lee, S.T.; Welch, K.D.; Cook, D.; Kem, W.R. Activation and Desensitization of Peripheral Muscle and Neuronal Nicotinic Acetylcholine Receptors by Selected, Naturally-Occurring Pyridine Alkaloids. Toxins 2016, 8, 204.

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