The perhydro derivative of histrionicotoxin reversibly blocks the excitatory 
ionic transduction system in the synaptic and sarcolemmal membranes of mammalian 
skeletal muscle cells. The efficacy of perhydrohistrionicotoxin as an antagonist 
at the post-synaptic membrane is increased by the transient presence of 
acetylcholine in the endplate of innervated muscles and at extrajunctional 
receptors in denervated muscles. alpha-Bungarotoxin and 
[(3)H]monoacetyl-alpha-bungarotoxin block the endplate acetylcholine receptors, 
each binding to the same extent. The effect of bungarotoxin is partially 
reversible. These electrophysiological results, together with the effects of 
perhydrohistrionicotoxin and/or d-tubocurarine on the binding of 
[(3)H]monoacetyl-alpha-bungarotoxin at endplates of murine diaphragm muscle and 
on the bungarotoxin-elicited irreversible blockade of neuromuscular 
transmission, suggest that at least two types of sites participate in the 
synaptic excitation by acetylcholine. One site, competitively blocked by 
bungarotoxin and by curare, is presumably the acetylcholine receptor. Binding of 
bungarotoxin at this site is responsible for an irreversible blockade of 
neuromuscular transmission. The second site, competitively blocked by 
bungarotoxin and perhydrohistrionicotoxin, is proposed to be part of the 
cholinergic ion conductance modulator. Binding of bungarotoxin to this site does 
not result in an irreversible blockade.