Interactions of Sea Anemone Toxins with Insect Sodium Channel-Insights from Electrophysiology and Molecular Docking Studies.

Beata Niklas,Maria Stankiewicz,Milena Jankowska,László Béress,Dalia Gordon,Wieslaw Nowak

doi:10.3390/molecules26051302

Abstract

Animal venoms are considered as a promising source of new drugs. Sea anemones release polypeptides that affect electrical activity of neurons of their prey. Voltage dependent sodium (Nav) channels are the common targets of Av1, Av2, and Av3 toxins from Anemonia viridis and CgNa from Condylactis gigantea. The toxins bind to the extracellular side of a channel and slow its fast inactivation, but molecular details of the binding modes are not known. Electrophysiological measurements on Periplaneta americana neuronal preparation revealed differences in potency of these toxins to increase nerve activity. Av1 and CgNa exhibit the strongest effects, while Av2 the weakest effect. Extensive molecular docking using a modern SMINA computer method revealed only partial overlap among the sets of toxins’ and channel’s amino acid residues responsible for the selectivity and binding modes. Docking positions support earlier supposition that the higher neuronal activity observed in electrophysiology should be attributed to hampering the fast inactivation gate by interactions of an anemone toxin with the voltage driven S4 helix from domain IV of cockroach Nav channel (NavPaS). Our modelling provides new data linking activity of toxins with their mode of binding in site 3 of NavPaS channel.

Highlights

Voltage dependent sodium (Nav) channels are cell transmembrane proteins responsible for the depolarizing phase of action potentials which are carriers of information in excitable tissues
The four sea anemone toxins differ in sequence and structure (Supplementary Information (SI), Figure S1); we set to compare their effectiveness in physiological conditions
The toxins Av1 and Av2 and Av3 were isolated from sea anemone Anemonia viridis venom [61], CgNa toxin was isolated from the Condylactis gigantea venom [62]

Summary

Introduction

Voltage dependent sodium (Nav) channels are cell transmembrane proteins responsible for the depolarizing phase of action potentials which are carriers of information in excitable tissues. Nav channel structure consist of a single polypeptide chain that folds into four domains (DI–DIV) with six transmembrane helices (S1–S6) each. The outward movement of positively charged S4 helices generates the gating current which triggers the activation of the sodium channel [1]. When S4 helices are raised outwards, the intracellular IG quickly blocks sodium ions entry into the neuron in a process named fast inactivation (completed within 1–2 ms). Due to this blocking mechanism, neurons exhibit very short action potentials and, enable a high frequency of signal transmission [2]. In vertebrates, the IG gate, located in DIII-DIV linker, consists of Isoleucine-

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