Functional Anatomy of Scorpion Toxins Affecting Sodium Channels

Gordon, Dalia; Savarin, Philippe; Gurevitz, Michael; Zinn‐Justin, Sophie

doi:10.3109/15569549809009247

Cited by 181 publications

(225 citation statements)

References 82 publications

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“…Low Lqh␤1 concentrations inhibited the binding of 125 I-His-Css4 (K i ϭ 0.51 Ϯ 0.27 nM; n ϭ 3), indicating that the two toxins competed for binding to receptor site 4 (Fig. 2), which is recognized by all scorpion ␤-toxins (4,30). In contrast, Lqh2, which binds to receptor site 3 on Na v s (20), did not inhibit 125 I-His-Css4 binding to rat brain synaptosomes (Fig.…”

Section: Expression and Characterization Of Recombinantmentioning

confidence: 99%

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

Cohen

Karbat

Gilles

et al. 2005

Journal of Biological Chemistry

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125

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Scorpion ␤-toxins that affect the activation of mammalian voltage-gated sodium channels (Na v s) have been studied extensively, but little is known about their functional surface and mode of interaction with the channel receptor. To enable a molecular approach to this question, we have established a successful expression system for the anti-mammalian scorpion ␤-toxin, Css4, whose effects on rat brain Na v s have been well characterized. A recombinant toxin, His-Css4, was obtained when fused to a His tag and a thrombin cleavage site and had similar binding affinity for and effect on Na currents of rat brain sodium channels as those of the native toxin isolated from the scorpion venom. Molecular dissection of His-Css4 elucidated a functional surface of 1245 Å 2 composed of the following: 1) a cluster of residues associated with the ␣-helix, which includes a putative "hot spot" (this cluster is conserved among scorpion ␤-toxins and contains their "pharmacophore"); 2) a hydrophobic cluster associated mainly with the ␤2 and ␤3 strands, which is likely to confer the specificity for mammalian Na v s; 3) a single bioactive residue (Trp-58) in the C-tail; and 4) a negatively charged residue (Glu-15) involved in voltage sensor trapping as inferred from our ability to uncouple toxin binding from activity upon its substitution. This study expands our understanding about the mode of action of scorpion ␤-toxins and illuminates differences in the functional surfaces that may dictate their specificities for mammalian versus insect sodium channels.

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Section: Expression and Characterization Of Recombinantmentioning

confidence: 99%

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

Cohen

Karbat

Gilles

et al. 2005

Journal of Biological Chemistry

Self Cite

125

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“…Scorpion α-like toxins belong to the same group but distinguish themselves by acting on both mammals and insects. However, they do not bind to rat brain synaptosomes (Gordon et al, 1996;Gordon, 1998;Possani et al, 1999). The nomenclature of these α-like toxins is primarily based on the results of binding displacement studies, while the properties of α-and α-like toxins from an electrophysiological point of view are in fact alike (Couraud et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Bosmans

Martin‐Eauclaire²,

Tytgat

2007

Toxicology and Applied Pharmacology

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In general, scorpion β-toxins have been well examined. However, few in-depth studies have been devoted to species selectivity and affinity comparisons on the different voltage-activated Na + channels since they have become available as cloned channels that can be studied in heterologous expression systems. As a result, their classification is largely historical and dates from early in vivo experiments on mice and cockroach and fly larvae.In this study, we aimed to provide an updated overview of selectivity and affinity of scorpion β-toxins towards voltage-activated Na + channels of vertebrates or invertebrates. As pharmacological tools, we used the classic β-toxins AaHIT, Css II, Css IV, Css VI and Ts VII and tested them on the neuronal vertebrate voltage-activated Na + channel, rNa v 1.2a. For comparison, its invertebrate counterpart, DmNav1, was also tested. Both these channels were expressed in Xenopus laevis oocytes and the currents measured with the two-electrode voltage-clamp technique. We supplemented this data with several binding displacement studies on rat brain synaptosomes. The results lead us to propose a general classification and a novel nomenclature of scorpion β-toxins based on pharmacological activity.

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“…Na V channels play a pivotal role in cellular excitability and are targeted by a large variety of chemically distinct toxins (Janiszewski, 1990;Catterall, 1992;Gordon et al, 1998). Understanding the molecular mechanisms underlying the toxin action is not only important for toxicological research; various toxic substances serve as lead structures for novel therapeutics such as analgesics.…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular biophysics

2006

Choice Reviews Online

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Functional Anatomy of Scorpion Toxins Affecting Sodium Channels

Cited by 181 publications

References 82 publications

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

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

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

Molecular and cellular biophysics

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