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The Journal of Neuroscience, October 15, 1999, 19(20):8730-8739

A Scorpion -Like Toxin That Is Active on Insects and Mammals Reveals an Unexpected Specificity and Distribution of Sodium Channel Subtypes in Rat Brain Neurons

Nicolas Gilles¹, Christophe Blanchet², Iris Shichor³, Marc Zaninetti², Ilana Lotan³, Daniel Bertrand², and Dalia Gordon¹

¹ CEA, Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines, Saclay 91191, France, ² Department of Physiology, C. M. U., CH 1211 Geneva 4, Switzerland, and ³ Tel-Aviv University, Sackler School of Medicine, Department of Physiology and Pharmacology, Ramat Aviv, 69978 Israel

Several scorpion toxins have been shown to exert their neurotoxic effects by a direct interaction with voltage-dependent sodium channels. Both classical scorpion -toxins such as Lqh II from Leiurus quiquestratus hebraeus and -like toxins as toxin III from the same scorpion (Lqh III) competitively interact for binding on receptor site 3 of insect sodium channels. Conversely, Lqh III, which is highly toxic in mammalian brain, reveals no specific 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 Lqh III binding sites distinct from those present in synaptosomes must exist in the brain. In agreement, electrophysiological experiments performed on acute rat hippocampal slices revealed that Lqh III strongly affects the inactivation of voltage-gated sodium channels recorded either in current or voltage clamp, whereas Lqh II had weak, or no, effects. In contrast, Lqh III had no effect on cultured embryonic chick central neurons and on sodium channels from rat brain IIA and 1 subunits reconstituted in Xenopus oocytes, whereas sea anemone toxin ATXII and Lqh II were very active. These data indicate that the -like toxin Lqh III displays a surprising subtype specificity, reveals the presence of a new, distinct sodium channel insensitive to Lqh II, and highlights the differences in distribution of channel expression in the CNS. This toxin may constitute a valuable tool for the investigation of mammalian brain function.

Key words: scorpion -toxin; scorpion -like toxin; sodium channel subtypes; receptor site 3; hippocampus slices; expression in oocytes; chick central neurons; insect sodium channels; rat brain synaptosomes

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19208730-10$05.00/0

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