Peptides isolated from the venom of Conus geographus block neuromuscular transmission

The effects of a mixture of two peptides (GI and GII), purified from the venom of the marine gastropod, Conus geographus, were studied on neuromuscular transmission in the isolated mouse phrenic nerve--diaphragm and frog sciatic nerve--sartorius muscles. The GI--GII mixture rapidly blocked nerve-evoked contractions of the mouse diaphragm at bath concentrations greater than or equal to 0.2 microM but had no effect on contractions elicited by direct muscle stimulation. Paralytic concentrations of GI--GII had no significant effect on the compound nerve action potential of the bullfrog sciatic nerve. Similar concentrations of GI--GII produced a rapid reduction of endplate potential (epp) and miniature endplate potential amplitudes, apparently by a postsynaptic effect because the decrease in epp amplitude produced by subparalytic doses was not accompanied by significant alteration in the epp quantal content. The GI--GII mixture also inhibited [125I]alpha-bungarotoxin binding to endplate regions of the mouse diaphragm in a dose-dependent manner and was at least 10 times more potent than d-tubocurarine. We conclude that the blockage of vertebrate neuromuscular transmission by GI--GII is in part due to antagonism of acetylcholine binding to its receptor at motor endplates.