Waglerin-1 selectively blocks the epsilon form of the muscle nicotinic acetylcholine receptor

Neonatal mice resist the lethal effect of Waglerin-1. Because Waglerin-1 bl ocks the nicotinic acetylcholine receptor of mature end-plates, the appeara nce of lethality may result from the epsilon- for gamma-subunit substitutio n. In support of this hypothesis, adult knockout (KO) mice lacking the gene coding for the E-subunit resist the lethal effect of Waglerin-1. In contra st, heterozygous litter mates respond to Waglerin-1 like adult wild-type mi ce. In vitro application of 1 mu M Waglerin-1 inhibited spontaneous miniatu re end-plate potentials and evoked end-plate potentials of adult wild-type and heterozygous KO mice. Both miniature end-plate potentials and end-plate potentials of neonatal wildtype and adult homozygous KO mice resisted Wagl erin-1. Waglerin-1 decreased the end-plate response of adult wild-type mice to iontophoretically applied acetylcholine (ACh) with an IC50 value of 50 nM; 1 mu M Waglerin-1 decreased the ACh response to 4 +/- 1% of control for adult heterozygous KO mice. In contrast, 1 mu M Waglerin-1 decreased the A Ch response to 73 +/- 2% of control for wild-type mice less than 11 days ol d and had no effect on the ACh response of adult homozygous KO mice. Betwee n 11 and 12 days after birth, the suppressant effect of Waglerin-1 on wild- type end-plate responses to ACh dramatically increased. Waglerin-1 reduced binding of alpha-bungarotoxin to end-plates of adult but not neonatal wild- type mice. These data demonstrate that Waglerin-1 selectively blocks the mo use muscle nicotinic acetylcholine receptor containing the epsilon-subunit.