title: Mammalian skeletal muscle voltage-gated sodium channels are affected by scorpion depressant "insect-selective" toxins when preconditioned.
abstract: Among scorpion beta- and alpha-toxins that modify the activation and inactivation of voltage-gated sodium channels (Na(v)s), depressant beta-toxins have traditionally been classified as anti-insect selective on the basis of toxicity assays and lack of binding and effect on mammalian Na(v)s. Here we show that the depressant beta-toxins LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus (Lqh) bind with nanomolar affinity to receptor site 4 on rat skeletal muscle Na(v)s, 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 rNa(v)1.4, expressed in Xenopus laevis oocytes, was modulated by the site 3 alpha-toxin LqhalphaIT, LqhIT2 was capable of inducing a negative shift in the voltage-dependence of activation after a short prepulse, as was shown for other beta-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 beta-toxins. Whereas substitutions E24A/N abolished the activity of both LqhIT2 and Lqh-dprIT3 at insect Na(v)s, 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.
authors.affiliation: Department of Plant Sciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv 69978, Tel-Aviv, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Cohen
authors.forename: Yael
authors.initials: Y
authors.lastname: Troub
authors.forename: Michael
authors.initials: M
authors.lastname: Turkov
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
authors.forename: Nitza
authors.initials: N
authors.lastname: Ilan
authors.forename: Morris
authors.initials: M
authors.lastname: Benveniste
authors.forename: Dalia
authors.initials: D
authors.lastname: Gordon
authors.forename: Michael
authors.initials: M
authors.lastname: Gurevitz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects*; D009154:Mutation; D009865:Oocytes; D051381:Rats; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C076349:LqhIT2 insect toxin; D009124:Muscle Proteins; C466180:Scn4a protein, rat; D012604:Scorpion Venoms; D015222:Sodium Channels