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ARS Home » Pacific West Area » Logan, Utah » Poisonous Plant Research » Research » Publications at this Location » Publication #294521
Title: The role of the a7 subunit of the nicotinic acetylcholine receptor in the acute toxicosis of methyllycaconitine in mice.

Author
item Welch, Kevin
item Green, Benedict - Ben
item Panter, Kip
item Pfister, James
item Gardner, Dale

Submitted to: Journal of Applied Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/20/2012
Publication Date: 9/1/2013
Citation: Welch, K.D., Green, B.T., Panter, K.E., Pfister, J.A., Gardner, D.R. 2013. The role of the a7 subunit of the nicotinic acetylcholine receptor in the acute toxicosis of methyllycaconitine in mice. Journal of Applied Toxicology. 33(9):1011-6.

Interpretive Summary: The toxicity of larkspur plants (Delphinium spp.) is due to the more than 18 norditerpenoid alkaloids, each with varying degrees of affinity, and potency at nicotinic acetylcholine receptors (nAChR). Research has demonstrated that the physiological effects of methyllycaconitine (MLA), one of the more abundant toxic alkaloids in larkspur, were attributable to its high affinity for nAChR ligand binding sites in muscle and nervous systems. Recent research demonstrated a correlation between the LD50 of MLA and the amount of a7 nAChR in various mouse strains, suggesting that mice with more a7 nAChR require a more MLA to be poisoned. The objective of this study was to characterize the role of the a7 subunit in the acute toxicosis of MLA by evaluating the acute toxicity of MLA in mice lacking the a7 subunit. The results of this study suggest that the a7 subunit of nAChRs does not play an integral role in the acute toxicosis of MLA. This suggests that the mechanism of action for the acute toxicity of these compounds is via interaction with other nAChR subunits, or that the knockout mice have developed a compensatory mechanism such that they were no longer dependent upon the a7 subunit. We postulate that the mechanism of action of these types of toxins is via direct inhibition of nAChRs at the neuromuscular junction, which does not involve the a7 subunit.

Technical Abstract: The adverse physiological effects of methyllycaconitine (MLA) have been attributed to its competitive antagonism of nicotinic acetylcholine receptors (nAChRs). Recent research demonstrated a correlation between the LD50 of MLA and the amount of a7 nAChR in various mouse strains, suggesting that mice with more a7 nAChR require a more MLA to be poisoned. The objective of this study was to characterize the role of the a7 subunit in the acute toxicosis of MLA by evaluating the acute toxicity of MLA in mice lacking the a7 subunit. The LD50 values for MLA were 4.2 ± 0.9, 3.7 ± 1.1, and 3.3 ± 0.9 mg/kg BW for wild-type, heterozygous knockout, and homozygous knockout mice, respectively. We also evaluated the response of anabasine in these mice. The LD50 values for anabasine were 1.6 ± 0.3, 2.0 ± 0.4, and 1.8 ± 0.3 mg/kg BW for wild-type, heterozygous knockout, and homozygous knockout mice, respectively. The protein expression of various nAChR subunits was compared to determine if mice lacking the a7 subunit compensate by over expressing other nAChR subunits. There were no significant differences in the protein expression of a3, a4, a5, ß2, and ß4 subunits amongst the three genotypes of mice in brain or skeletal muscle. The results of this study suggest that a7 nAChR does not play an integral role in the acute toxicosis of MLA or anabasine. Consequently other nAChR subunits of nAChRs found in the neuromuscular junction are likely the primary target for MLA and anabasine resulting in acute toxicosis.