RT Journal Article SR Electronic T1 Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant “Insect-Selective” Toxins when Preconditioned JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1220 OP 1227 DO 10.1124/mol.107.039057 VO 72 IS 5 A1 Lior Cohen A1 Yael Troub A1 Michael Turkov A1 Nicolas Gilles A1 Nitza Ilan A1 Morris Benveniste A1 Dalia Gordon A1 Michael Gurevitz YR 2007 UL http://molpharm.aspetjournals.org/content/72/5/1220.abstract AB Among scorpion β- and α-toxins that modify the activation and inactivation of voltage-gated sodium channels (Navs), depressant β-toxins have traditionally been classified as anti-insect selective on the basis of toxicity assays and lack of binding and effect on mammalian Navs. Here we show that the depressant β-toxins LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus (Lqh) bind with nanomolar affinity to receptor site 4 on rat skeletal muscle Navs, but their effect on the gating properties can be viewed only after channel preconditioning, such as that rendered by a long depolarizing prepulse. This observation explains the lack of toxicity when depressant toxins are injected in mice. However, when the muscle channel rNav1.4, expressed in Xenopus laevis oocytes, was modulated by the site 3 α-toxin LqhαIT, LqhIT2 was capable of inducing a negative shift in the voltage-dependence of activation after a short prepulse, as was shown for other β-toxins. These unprecedented results suggest that depressant toxins may have a toxic impact on mammals in the context of the complete scorpion venom. To assess whether LqhIT2 and Lqh-dprIT3 interact with the insect and rat muscle channels in a similar manner, we examined the role of Glu24, a conserved “hot spot” at the bioactive surface of β-toxins. Whereas substitutions E24A/N abolished the activity of both LqhIT2 and Lqh-dprIT3 at insect Navs, they increased the affinity of the toxins for rat skeletal muscle channels. This result implies that depressant toxins interact differently with the two channel types and that substitution of Glu24 is essential for converting toxin selectivity. The American Society for Pharmacology and Experimental Therapeutics