A scorpion alpha-like toxin that is active on insects and mammals reveals an unexpected specificity and distribution of sodium channel subtypes in rat brain neurons

Several scorpion toxins have been shown to exert their neurotoxic effects b y a direct interaction with voltage-dependent sodium channels. Both classic al scorpion alpha-toxins such as Lqh II from Leiurus quiquestratus hebraeus and alpha-like toxins as toxin III from the same scorpion (Lqh III) compet itively interact for binding on receptor site 3 of insect sodium channels. Conversely, Lqh III, which is highly toxic in mammalian brain, reveals no s pecific binding to sodium channels of rat brain synaptosomes and displaces the binding of Lqh II only at high concentration. The contrast between the low-affinity interaction and the high toxicity of Lqh III indicates that Lq h III binding sites distinct from those present in synaptosomes must exist in the brain. In agreement, electrophysiological experiments performed on a cute rat hippocampal slices revealed that Lqh III strongly affects the inac tivation of voltage-gated sodium channels recorded either in current or vol tage clamp, whereas Lqh II had weak, or no, effects. In contrast, Lqh III h ad no effect on cultured embryonic chick central neurons and on sodium chan nels from rat brain IIA and beta 1 subunits reconstituted in Xenopus oocyte s, whereas sea anemone toxin ATXII and Lqh II were very active. These data indicate that the alpha-like toxin Lqh III displays a surprising subtype sp ecificity, reveals the presence of a new, distinct sodium channel insensiti ve to Lqh II, and highlights the differences in distribution of channel exp ression in the CNS. This toxin may constitute a valuable tool for the inves tigation of mammalian brain function.