Abstract
At least six topologically separated neurotoxin receptor sites have been identified on sodium channels that reveal strong allosteric interactions among them. We have studied the allosteric modulation induced by veratridine, binding to receptor site 2, and brevetoxin PbTx-1, occupying receptor site 5, on the binding of alpha-scorpion toxins at receptor site 3, on three different neuronal sodium channels: rat brain, locust, and cockroach synaptosomes. We used 125I-AaH II, the most active alpha-scorpion toxin on vertebrates, and 125I-Lqh alpha IT, shown to have high activity on insects, as specific probes for receptor site 3 in rat brain and insect sodium channels. Our results reveal that brevetoxin PbTx-1 generates three types of effects at receptor site 3:1) negative allosteric modulation in rat brain sodium channels, 2) positive modulation in locust sodium channels, and 3) no effect on cockroach sodium channel. However, PbTx-1 activates sodium channels in cockroach axon similarly to its activity in other preparation. Veratridine positively modulates both rat brain and locust sodium channels but had no effect on alpha-toxin binding in cockroach. The dramatic differences in allosteric modulations in each sodium channel subtype suggest structural differences in receptor sites for PbTx-1 and/or at the coupling regions with alpha-scorpion toxin receptor sites in the different sodium channels, which can be detected by combined application of specific channel modifiers and may elucidate the dynamic gating activity and the mechanism of allosteric interactions among various neurotoxin receptors.
Highlights
A-Scorpion Toxins Binding on Rat Brain and Insect Sodium Channels Reveal Divergent Allosteric Modulations by Brevetoxin and Veratridine*
The dramatic differences in allosteric modulations in each sodium channel subtype suggest structural differences in receptor sites for PbTx-l and/or at the coupling regions with a-scorpion toxin receptor sites in the different sodium channels, which can be detected by combined application of specific channel modifiers and may elucidate the dynamic gating activity and the mechanism ofallosteric interactions among various neurotoxin receptors
The present study examines, for the first time, the allosteric interactions that occur among three distinct, identified receptor sites on sodium channels in different animal phyla in mammals and in insects
Summary
We have studied the allosteric modulation induced by veratridine, binding to receptor site 2, and brevetoxin PbTx-l, occupying receptor site 5, on the binding of a-scorpion toxins at receptor site 3, on three different neuronal sodium channels: rat brain, locust, and cockroach synaptosomes. PbTx-l activates sodium channels in cockroach axon to its activity in other preparation Veratridine positively modulates both rat brain and locust sodium channels but had no effect on a-toxin binding in cockroach. As a critical element in nerve excitability, sodium channels serve as specific targets for many neurotoxins These toxins occupy different receptor sites on the sodium channel and have been used as tools for functional mapping and characterization of the channel
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