Activation of the Voltage‐Sensitive Sodium Channel by a β‐Scorpion Toxin in Rat Brain Nerve‐Ending Particles

Abstract

Neurotoxins purified from scorpion venoms previously had been divided into two classes according to their binding properties in rat brain synaptosomes. However, the pharmacological action of β‐scorpion toxin (β‐ScTx) on this preparation has not yet been described. In this report we show that a β‐ScTx induced an increase in 22Na+ uptake through synaptosomal voltage‐sensitive sodium channels since this stimulation was abolished by tetrodotoxin (TTX). The increase was smaller than with veratridine and no synergy was observed between β‐ScTx and veratridine, as is the case for α‐scorpion toxin (α‐ScTx) and veratridine. The effects of α‐ and β‐ScTx were additive and the concentration‐effect curves for each type of toxin were not modified by the other, suggesting that these two types of toxins act through distinct and noninteracting receptor sites. This was confirmed by the absence of mutual modification of the equilibrium and kinetic binding properties. β‐ScTx was shown to inhibit the uptake and to stimulate the release of [3H]γ‐aminobutyric acid. These effects were blocked by TTX, and no synergy was observed with veratridine. It was concluded that all these effects are mediated by the activation of voltagesensitive sodium channels induced by the binding of β‐ScTx to a receptor site (site 4) distinct from those for other neurotoxins acting on sodium channels.

µO-Conotoxins Inhibit NaVChannels by Interfering with their Voltage Sensors in Domain-2

“…This interaction pattern of µO-conotoxins with epitopes in domain-2 and domain-3 of Na V channels is reminiscent of scorpion b-toxins for which these binding epitopes were originally termed receptor site-4 (RS4). 36 However, in contrast to µO-conotoxins, the major functional impact of b-toxins is to cause subthreshold channel openings by stabilizing an activated conformation of the voltage sensor in domain-2, termed voltage-sensor trapping. 11 Here we utilized the different modes of action of the µO-conotoxin MrVIA ("channel block") and of the scorpion b-toxin Ts1 ("activation shift") to test if both toxins compete for modifying the channel function.…”