Scorpion Toxins Affecting Sodium Current Inactivation Bind to Distinct Homologous Receptor Sites on Rat Brain and Insect Sodium Channels

Abstract

Sodium channels posses receptor sites for many neurotoxins, of which several groups were shown to inhibit sodium current inactivation. Receptor sites that bind ␣-and ␣-like scorpion toxins are of particular interest since neurotoxin binding at these extracellular regions can affect the inactivation process at intramembranal segments of the channel. We examined, for the first time, the interaction of different scorpion neurotoxins, all affecting sodium current inactivation and toxic to mammals, with ␣-scorpion toxin receptor sites on both mammalian and insect sodium channels. As specific probes for rat and insect sodium channels, we used the radiolabeled ␣-scorpion toxins AaH II and Lqh␣IT, the most active ␣-toxins on mammals and insect, respectively. We demonstrate that the different scorpion toxins may be classified to several groups, according to their in vivo and in vitro activity on mammalian and insect sodium channels. Analysis of competitive binding interaction reveal that each group may occupy a distinct receptor site on sodium channels. The ␣-mammal scorpion toxins and the anti-insect Lqh␣IT bind to homologous but not identical receptor sites on both rat brain and insect sodium channels. Sea anemone toxin ATX II, previously considered to share receptor site 3 with ␣-scorpion toxins, is suggested to bind to a partially overlapping receptor site with both AaH II and Lqh␣IT. Competitive binding interactions with other scorpion toxins suggest the presence of a putative additional receptor site on sodium channels, which may bind a unique group of these scorpion toxins (Bom III and IV), active on both mammals and insects. We suggest the presence of a cluster of receptor sites for scorpion toxins that inhibit sodium current inactivation, which is very similar on insect and rat brain sodium channels, in spite of the structural and pharmacological differences between them. The sea anemone toxin ATX II is also suggested to bind within this cluster.

Differential susceptibilities of human lung, breast and skin cancer cell lines to killing by five sea anemone venoms

“…Some anemones also contain smaller peptide toxins that selectively block specific potassium channels. Most anemones also contain potent cytolytic proteins called actinoporins, which permeabilize cell membranes and ultimately cause cell death (6,9). The use of toxins and venoms as the basis of natural products can provide new biomedical research tools and unique molecular models for designing anticancer drugs (10,11).…”

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

“…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).…”

The Sophisticated Peptide Chemistry of Venomous Animals as a Source of Novel Insecticides Acting on Voltage-Gated Sodium Channels

“…5). Several studies have demonstrated the functionally relevant structural differences in insect and mammalian receptor site 3 regions (Gordon et al, 1996). Although more structure-function work is necessary to completely unravel these structural differences, these phyla depending differences do support the arguments to target site 3 in the search for new Na V channel acting insecticides (Cohen et al, 2006).…”

“…Another toxin from the same sea anemone, ATX-II is toxic to both insect and mammalian Na V channels. However, its binding affinity for cockroach neuronal membranes is very high whereas its binding affinity for rat brain synaptosomes is low (Gordon et al, 1996). Furthermore, ATX-II binds with extreme high potency to site 3 of insect Na V channels, resulting in a strong slowing down of the fast inactivation (Warmke et al, 1997).…”