Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Food Science & Technology, Toxicology, sea anemone, type II toxins, voltage-gated sodium channels, electrophysiology, AMINO-ACID-SEQUENCE, SODIUM-CHANNELS, ANTHOPLEURIN-B, RADIANTHUS-MACRODACTYLUS, 3-DIMENSIONAL STRUCTURE, PEPTIDE TOXINS, NEUROTOXIN, PROTEASE, INACTIVATION, TOXICITY, Amino Acid Sequence, Animals, Binding Sites, Cell Line, Cnidarian Venoms, Ion Channel Gating, Peptides, Sea Anemones, Sodium Channels, Structure-Activity Relationship, Toxins, Biological, PDM/19/164#55254451, 0601 Biochemistry and Cell Biology, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

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.