Abstract
Toxins modulating NaV channels are the most abundant and studied peptide components of sea anemone venom. Three type-II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and RTX-VI, were isolated from the sea anemone Heteractis crispa. RTX-VI has been found to be an unusual analog of RTX-III. The electrophysiological effects of Heteractis toxins on nine NaV subtypes were investigated for the first time. Heteractis toxins mainly affect the inactivation of the mammalian NaV channels expressed in the central nervous system (NaV1.1–NaV1.3, NaV1.6) as well as insect and arachnid channels (BgNaV1, VdNaV1). The absence of Arg13 in the RTX-VI structure does not prevent toxin binding with the channel but it has changed its pharmacological profile and potency. According to computer modeling data, the δ-SHTX-Hcr1f binds within the extracellular region of the rNaV1.2 voltage-sensing domain IV and pore-forming domain I through a network of strong interactions, and an additional fixation of the toxin at the channel binding site is carried out through the phospholipid environment. Our data suggest that Heteractis toxins could be used as molecular tools for NaV channel studies or insecticides rather than as pharmacological agents.
Highlights
Voltage-gated sodium channels (NaV ) are key elements for the transmission of electrical signals, as they initiate and propagate action potentials in excitable neuronal, cardiac, and skeletal muscle cells.NaV channels have non-canonical functions in non-excitable cells [1,2]
In the current paper we describe the isolation, structural, and functional characterization of two known type II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and a new one, RTX-VI, from the sea anemone
The separation of fractions 1 and 3 (Figure 1b) by RP-HPLC resulted in peptides with molecular masses corresponding to the type II toxins RpII
Summary
Voltage-gated sodium channels (NaV ) are key elements for the transmission of electrical signals, as they initiate and propagate action potentials in excitable neuronal, cardiac, and skeletal muscle cells. All sea anemone toxins are suggested to bind within site 3 of NaV. Peptide association to the ion channels is due to electrostatic interactions between amino acid residues of the toxin molecule and negatively charged residues within an extracellular link connecting the third and fourth transmembrane segments of the NaV domain IV [4]. In the current paper we describe the isolation, structural, and functional characterization of two known type II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and a new one, RTX-VI, from the sea anemone. Electrophysiological screening of these three toxins on NaV channel subtypes showed current activation of the CNS NaV (NaV 1.1–NaV 1.3, NaV 1.6), insect and arachnid (BgNaV 1, VdNaV 1) channels. Demonstrates that, despite the overlapping of the sea anemone toxin binding site with that of the scorpion α-toxin, the mode of action on the voltage-sensing domain IV (VSD-IV) is distinct
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