title: The role of the α7 subunit of the nicotinic acetylcholine receptor in the acute toxicosis of methyllycaconitine in mice.
abstract: The adverse physiological effects of methyllycaconitine (MLA) have been attributed to its competitive antagonism of nicotinic acetylcholine receptors (nAChRs). Recent research suggested a correlation between the lethal dose (LD50 ) of MLA and the amount of α7 nAChR in various mouse strains, suggesting that mice with more α7 nAChR require more MLA to be poisoned. The objective of this study was to characterize the role of the α7 subunit in the acute toxicosis of MLA by evaluating the acute toxicity of MLA in mice lacking the α7 subunit. The LD50 values for MLA were 4.2 ± 0.9, 3.7 ± 1.1 and 3.3 ± 0.9 mg kg(-1) body weight (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(-1) BW for wild-type, heterozygous knockout and homozygous knockout mice, respectively. The protein expresson of various nAChR subunits was compared to determine if mice lacking the α7 subunit compensate by over expressing other nAChR subunits. There were no significant differences in the protein expression of the α3 , α4 , α5 , β2 and β4 subunits amongst the three genotypes of mice in brain or skeletal muscle. The results of this study suggest that α7 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 probably the primary target for MLA and anabasine resulting in acute toxicosis.
authors.affiliation: USDA-ARS Poisonous Plant Research Laboratory, Logan, UT 84341, USA. Kevin.Welch@ars.usda.gov
authors.forename: K D
authors.initials: KD
authors.lastname: Welch
authors.forename: B T
authors.initials: BT
authors.lastname: Green
authors.forename: K E
authors.initials: KE
authors.lastname: Panter
authors.forename: J A
authors.initials: JA
authors.lastname: Pfister
authors.forename: D R
authors.initials: DR
authors.lastname: Gardner
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007928:Lethal Dose 50; D016015:Logistic Models; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023382:Toxicity Tests, Acute; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D000157:Aconitine
keywords: LD50; anabasine; delphinium; larkspur; methyllycaconitine; α7 nAChR