The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation

Abstract

Many human cardiovascular and neurological disorders (such as ischemia, epileptic seizures, traumatic brain injury, neuropathic pain, etc.) are associated with the abnormal functional activity of voltage-gated sodium channels (VGSCs/NaVs). Many natural toxins, including the sea anemone toxins (called neurotoxins), are an indispensable and promising tool in pharmacological researches. They have widely been carried out over the past three decades, in particular, in establishing different NaV subtypes functional properties and a specific role in various pathologies. Therefore, a large number of publications are currently dedicated to the search and study of the structure-functional relationships of new sea anemone natural neurotoxins–potential pharmacologically active compounds that specifically interact with various subtypes of voltage gated sodium channels as drug discovery targets. This review presents and summarizes some updated data on the structure-functional relationships of known sea anemone neurotoxins belonging to four structural types. The review also emphasizes the study of type 2 neurotoxins, produced by the tropical sea anemone Heteractis crispa, five structurally homologous and one unique double-stranded peptide that, due to the absence of a functionally significant Arg14 residue, loses toxicity but retains the ability to modulate several VGSCs subtypes.

Conductance Changes of Na+ Channels during the Late Na+ Current Flowing under Action Potential Voltage Clamp Conditions in Canine, Rabbit, and Guinea Pig Ventricular Myocytes

“…Current integrals, however, were significantly reduced by both nisoldipine and BAPTA (−48.5 ± 5 mC/F vs. −63.9 ± 6 mC/F and −46.7 ± 5 vs. −63.9 ± 6 mC/F, respectively). The toxin of Anemonia sulcata (Anemone toxin II, ATX-II) induces a current in cardiac tissues closely resembling INa,late by inhibiting the fast inactivation mechanism of Na + channels [37,38]. Therefore, the effect of 10 nM ATX-II in guinea pig and 1 nM ATX-II in canine myocytes were studied (Figure 6).…”

“…This demonstrates that the sodium channels in canine myocytes are more sensitive to ATX-II exposure than the channels in guinea pig cells. ATX-II lengthened the AP and increased the amplitude of INa,late in both species (Figure 6A The toxin of Anemonia sulcata (Anemone toxin II, ATX-II) induces a current in cardiac tissues closely resembling I Na,late by inhibiting the fast inactivation mechanism of Na + channels [37,38]. Therefore, the effect of 10 nM ATX-II in guinea pig and 1 nM ATX-II in canine myocytes were studied (Figure 6).…”

Marine Bioprospecting: Enzymes and Stress Proteins from the Sea Anemones Anthopleura dowii and Lebrunia neglecta

“…While sea anemones have long been recognized as rich sources of polypeptides with various pharmacological activities, it was not until a few years ago that proteomic and transcriptomic methods were implemented to explore the proteins in their secretions and tissues [29,31,32]. Bioprospecting in these venomous marine invertebrates has traditionally focused on polypeptides with neurotoxic [33,34] and cytotoxic properties [35], with little attention given to other components of biotechnological interest, such as enzymes, amylases [36], chitinases [37], proteases [29,31], oxidoreductases [38,39], heat shock proteins [40], and structural proteins [41], which have been identified in their crude venom extracts (CVEs) and secretions. These enzymes can potentially be used to develop tools for medical and industrial applications [42,43].…”