An 'Old World' scorpion β-toxin that recognizes both insect and mammalian sodium channels: A possible link towards diversification of β-toxins

Scorpion toxins that affect sodium channel (NaCh) gating in excitable cells are divided into α- and α-classes. Whereas α-toxins have been found in scorpions throughout the world, anti-mammalian β-toxins have been assigned, thus far, to 'New World' scorpions while anti-insect selective β-toxins (depressant and excitatory) have been described only in the 'Old World'. This distribution suggested that diversification of β-toxins into distinct pharmacological groups occurred after the separation of the continents, 150 million years ago. We have characterized a unique toxin, Lqhβ1, from the 'Old World' scorpion, Leiurus quinquestriatus hebraeus, that resembles in sequence and activity both 'New World' β-toxins as well as 'Old World' depressant toxins. Lqhβ1 competes, with apparent high affinity, with anti-insect and anti-mammalian β-toxins for binding to cockroach and rat brain synaptosomes, respectively. Surprisingly, Lqhβ1 also competes with an anti-mammalian α-toxin on binding to rat brain NaChs. Analysis of Lqhβ1 effects on rat brain and Drosophila Para NaChs expressed in Xenopus oocytes revealed a shift in the voltage-dependence of activation to more negative membrane potentials and a reduction in sodium peak currents in a manner typifying β-toxin activity. Moreover, Lqhβ1 resembles β-toxins by having a weak effect on cardiac NaChs and a marked effect on rat brain and skeletal muscle NaChs. These multifaceted features suggest that Lqhβ1 may represent an ancestral β-toxin group in 'Old World' scorpions that gave rise, after the separation of the continents, to depressant toxins in 'Old World' scorpions and to various β-toxin subgroups in 'New World' scorpions.