Catterall_1985_Toxicon_23_497

Measurements of neurotoxin-activated 22Na influx in neuroblastoma cells and neurotoxin binding in synaptosomes were used to define the site and mechanism of action of brevetoxins on sodium channels. Brevetoxin A alone did not enhance the sodium permeability of neuroblastoma cells, but markedly enhanced persistent activation of sodium channels by veratridine, aconitine and batrachotoxin, which act at neurotoxin receptor site 2. Enhancement of batrachotoxin action was accompanied by a 4.3-fold increase in the binding of [3H]batrachotoxinin A 20-alpha-benzoate to receptor site 2 on sodium channels in synaptosomes. These results point to an allosteric mechanism of brevetoxin action involving preferential binding to active states of sodium channels which have high affinity for neurotoxins, causing persistent activation of sodium channels at receptor site 2. Brevetoxin A does not block [3H]saxitoxin binding at neurotoxin receptor site 1 or 125I-labeled scorpion toxin binding at neurotoxin receptor site 3. The brevetoxins appear to act at a new neurotoxin receptor site on the sodium channel.