title: Activation and Desensitization of Peripheral Muscle and Neuronal Nicotinic Acetylcholine Receptors by Selected, Naturally-Occurring Pyridine Alkaloids.
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.
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N., Logan, UT 84341, USA. ben.green@ars.usda.gov.
authors.forename: Benedict T
authors.initials: BT
authors.lastname: Green
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N., Logan, UT 84341, USA. stephen.lee@ars.usda.gov.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N., Logan, UT 84341, USA. kevin.welch@ars.usda.gov.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Welch
authors.affiliation: Poisonous Plant Research Laboratory, Agricultural Research Service, United States Department of Agriculture, 1150 E. 1400 N., Logan, UT 84341, USA. daniel.cook@ars.usda.gov.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cook
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, 1200 Newell Road, Gainesville, FL 32610-0267, USA. wrkem@ufl.edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Kem
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006801:Humans; D008564:Membrane Potentials; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D018570:Risk Assessment; D013723:Teratogens / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D013723:Teratogens; D009538:Nicotine; C091713:anabaseine; D000691:Anabasine; C082748:epibatidine
keywords: anabaseine; anabasine; epibatidine; nicotine; nicotinic acetylcholine receptor; pyridine alkaloid