PT  - JOURNAL ARTICLE
AU  - Cohen, Lior
AU  - Troub, Yael
AU  - Turkov, Michael
AU  - Gilles, Nicolas
AU  - Ilan, Nitza
AU  - Benveniste, Morris
AU  - Gordon, Dalia
AU  - Gurevitz, Michael
TI  - Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant “Insect-Selective” Toxins when Preconditioned
AID  - 10.1124/mol.107.039057
DP  - 2007 Nov 01
TA  - Molecular Pharmacology
PG  - 1220--1227
VI  - 72
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/72/5/1220.short
4100  - http://molpharm.aspetjournals.org/content/72/5/1220.full
SO  - Mol Pharmacol2007 Nov 01; 72
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