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ARS Home » Pacific West Area » Logan, Utah » Poisonous Plant Research » Research » Publications at this Location » Publication #283621
Title: Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine

Author
item Green, Benedict - Ben
item Lee, Stephen
item Welch, Kevin
item Pfister, James
item Panter, Kip

Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/17/2012
Publication Date: 1/1/2013
Citation: Green, B.T., Lee, S.T., Welch, K.D., Pfister, J.A., Panter, K.E. 2013. Fetal-muscle type nicotinic acetylcholine receptor activation in TE-671 cells, and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine. Journal of Pharmacology and Experimental Therapeutics. 344:1-13.

Interpretive Summary: Coniine is an alkaloid found in poison hemlock (Conium maculatum L.). This alkaloid causes deformities in developing animals by the binding, activating, and desensitizing fetal muscle-type nicotinic acetylcholine receptors (nAChR). However, direct evidence of coniine actions at fetal-muscle type nAChR is lacking. This study compared coniine and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in cells Coniine was effective at eliciting electrical changes in cells and inhibiting fetal movement. Nicotine did not inhibit fetal movement in a day 40 pregnant goat model. Selective blockade of coniine actions was demonstrated in cells with conotoxins, which blocked the actions of coniine. These results provide evidence that coniine is acting at fetal muscle-type nAChR in a concentration dependent manner to inhibit fetal movement to cause deformities.

Technical Abstract: Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be due to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR which results in the complete inhibition of fetal movement. However, pharmacological evidence of coniine actions at fetal-muscle type nAChR is lacking. The present study compared (-)-coniine, (+)-coniine and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells which express fetal muscle-type nAChR. Further, alpha conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (-)-coniine in TE-671 cells. (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than (+)-coniine suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model suggesting agonist specificity for the inhibition of fetal movement. Selective antagonism was demonstrated in TE-671 cells with CTx EI and GI, which blocked the actions of both coniine enantiomers. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration dependent manner to inhibit fetal movement.