Nerve membrane sodium channels as the target site of brevetoxins at neuromuscular junctions.
Actions of two structurally related toxins, T-17 and brevetoxin-B, isolated from the red-tide dinoflagellate, Ptychodiscus brevis, were studied on the giant axon of the squid and the neuromuscular junctions of the frog and rat. T-17 toxin caused a large increase in the frequency of miniature endplate potentials at nanomolar concentrations. In one typical case with a frog endplate, the frequency increased from 1.9 s-1 before application of 3.5 nM T-17 to 69.3 s-1 within 5 min after application. In the rat muscle, the mean frequency increased from 1.39 s-1 in control to 11.93 s-1 after application of 23.2 nM T-17. The increase in miniature endplate potential frequency was reversed by the addition of 1 microM tetrodotoxin, and was not observed in a solution containing elevated Mg2+ and reduced Ca2+ concentrations. External or internal application of T-17 toxin (2-5 microM) or brevetoxin-B (10-30 microM) to intact or internally perfused squid axons caused a depolarization of the membrane. This depolarization was abolished by the removal of external Na+ or by addition of tetrodotoxin to the external solution. In voltage clamped squid giant axons, exposure to T-17 toxin or brevetoxin-B increased the non-inactivating component of the tetrodotoxin-sensitive sodium current. The sodium current was activated at potentials 15 to 40 mV more negative than control. It is proposed that these toxins modify a fraction of the sodium channels to a form which opens at potentials more negative than normal and which inactivates to a lesser extent. This mechanism would predict a depolarization of the nerve membrane at the neuromuscular junction, thus explaining the increased discharge of transmitter.
D000818:Animals; D001369:Axons / Q000187:drug effects; D049832:Decapodiformes; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008387:Marine Toxins / Q000494:pharmacology*; D009045:Motor Endplate / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism*; D035964:Oxocins; D011894:Rana pipiens; D051381:Rats; D011919:Rats, Inbred Strains; D000095702:Polyether Toxins
D007473:Ion Channels; D008387:Marine Toxins; D035964:Oxocins; C043466:brevetoxin B; D000095702:Polyether Toxins; C041017:brevetoxin T17