An ‘Old World’ scorpion β‐toxin that recognizes both insect and mammalian sodium channels

Abstract

Scorpion toxins that affect sodium channel (NaCh) gating in excitable cells are divided into a-and b-classes. Whereas a-toxins have been found in scorpions throughout the world, anti-mammalian b-toxins have been assigned, thus far, to ÔNew WorldÕ scorpions while anti-insect selective b-toxins (depressant and excitatory) have been described only in the ÔOld WorldÕ. 2This distribution suggested that diversification of b-toxins into distinct pharmacological groups occurred after the separation of the continents, 150 million years ago. We have characterized a unique toxin, Lqhb1, from the ÔOld WorldÕ scorpion, Leiurus quinquestriatus hebraeus, that resembles in sequence and activity both ÔNew WorldÕ b-toxins as well as ÔOld WorldÕ depressant toxins. Lqhb1 competes, with apparent high affinity, with anti-insect and anti-mammalian b-toxins for binding to cockroach and rat brain synaptosomes, respectively. Surprisingly, Lqhb1 also competes with an anti-mammalian a-toxin on binding to rat brain NaChs. Analysis of Lqhb1 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 b-toxin activity. Moreover, Lqhb1 resembles b-toxins by having a weak effect on cardiac NaChs and a marked effect on rat brain and skeletal muscle NaChs 3. These multifaceted features suggest that Lqhb1 may represent an ancestral b-toxin group in ÔOld WorldÕ scorpions that gave rise, after the separation of the continents, to depressant toxins in ÔOld WorldÕ scorpions and to various b-toxin subgroups in ÔNew WorldÕ scorpions.Keywords: scorpion toxins; sodium channel subtypes; toxin diversification.Scorpion Ôlong chainÕ toxins affecting voltage-gated sodium channels (NaCh) are polypeptides of 61-76 amino acids long that traditionally are divided between two major classes, a and b, according to their physiological effects on channel gating and their binding properties [1][2][3]. a-Toxins slow sodium channel inactivation upon binding to a homologous cluster of binding sites named receptor site-3, and are subdivided into distinct groups according to their potency for mammalian and insect receptors and their affinity for sodium channel subtypes [2,[4][5][6][7]. a-Toxins predominate in the venom of Buthidae scorpions of the ÔOld WorldÕ (Africa and Asia), but some representatives have been also identified in ÔNew WorldÕ (America) scorpions [1]. b-Toxins shift the activation voltage of sodium channels to more negative membrane potentials upon binding to receptor site-4 [2,7,8], and vary greatly in their effects on various animals. Css2 and Css4 (from Centruroides suffusus suffusus) show specificity for mammals [1]; Cll1 (from C. limpidus limpidus), Cn5, and Cn11 (from C. noxius) are highly effective on crustaceans [9-12]; Ts7 and Tst1 (from Tityus serrulatus and T. stigmurus), and Tbs1 and Tbs2 (from T. bahiensis) are highly effective on both insects and mammals [1,[12][13][14][15][16]...

Common Features in the Functional Surface of Scorpion β-Toxins and Elements That Confer Specificity for Insect and Mammalian Voltage-gated Sodium Channels

“…This common region, referred to as the pharmacophore of scorpion ␤-toxins, may explain their ability to compete to various extents on binding to receptor site 4 of different Na v s. Indeed, Cn2 competes with Bj-xtrIT on binding to insect Na v s (10), and Ts1 and Lqh␤1 compete with both excitatory and anti-mammalian ␤-toxins on binding to insect (40,41) and rat brain (28,33) neuronal preparations, respectively. Thus, the pharmacophore in various ␤-toxins is smaller than that predicted previously from the dissection of Bj-xtrIT (10) and consists of spatially conserved residues of similar chemical nature.…”

“…1A and 6B). Because all ␤-toxins induce a similar effect on channel activation (28,33,34,42,43), we assume they also trap the voltage sensor, but via different interactions.…”

The scorpion toxin Bot IX is a potent member of the α‐like family and has a unique N‐terminal sequence extension

“…previous reports in which other scorpion toxins able to bind to both VSDII and VSDIV have been described [7,12,[46][47][48].…”

In vivo and in vitro effects of scorpion venoms in Turkey: a mini-review

“…Scorpion toxins can change neuronal action potentials and cause the release of neurotransmitters from cholinergic and adrenergic neurons (4,(19)(20)(21)(22)(23)(24). Neurotoxins also disrupt synaptic vesicles, leading to the cessation of acetylcholine (ACh) release and to the blockage of neuromuscular transmission (18,23,25).…”

“…The scorpion toxins that affect sodium channels (NaCh) gating in excitable cells are divided into α and β classes. Alpha-toxins have been found in scorpions throughout the world, whereas anti-mammalian β-toxins have been assigned to New World scorpions and anti-insect selective β-toxins (depressant and excitatory) have been described only in the Old World (1)(2)(3)(4).…”