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

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.

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

“…Today, it is quite clear that the wide range of modulating action of NaTxs and the effect on the action potential duration of Na V s are due to their structural characteristics, surface electrostatic potential, and dipole moment [ 81 , 87 ]. Sodium channel toxins produced by sea anemones, neurotoxins, are currently the best characterized [ 1 , 2 , 4 , 7 , 13 , 14 , 22 , 35 , 37 , 39 , 58 , 80 , 88 , 89 ].…”

“…Although the 3D structure of the majority of NaTxs representing types 1, 2, and 4 has not yet been determined experimentally, high amino acid sequences identity and a common defensin-like fold stipulate their high conservation and structural similarity [ 148 ]. Despite the high similarity of neurotoxins amino acid sequences and 3D structures, their binding mechanisms to different sodium channel types may vary greatly [ 87 ]. Data on the secondary structure elements (alpha-helices and beta-sheets) of type 3 short neurotoxins are not known.…”

“…So far, not more than two or three NaTxs of structure type 2 have been investigated, using this approach. It is quite obvious that point substitutions in types 1 and 2 neurotoxin sequences and, in particular, the different distribution of positively and negatively charged residues can significantly change the value of the peptides dipole moment, which results in their specific interaction with certain targets, various Na V subtypes [ 81 , 87 ].…”

“…This Na V 1.2 binding site with δ-SHTX-Hcr1f also belongs to the extracellular region of the pore-forming PDI domain, whose Asp317, Gly318, Lys355, Asn285, and Asn340 residues interact with Asp7, Glu31, Arg45, Lys46, and Lys48 of the neurotoxin by means of the network of electrostatic interactions and hydrogen bonds [ 168 ]. Recently, similar binding of sea anemone neurotoxins Av1, Av2, Av3, and CgNa to a number of the PDI domain residues of the cockroach Na V PaS channel through the formation of hydrogen bonds and salt bridges has been found [ 87 ].…”

A Sea Anemone Lebrunia neglecta Venom Fraction Decreases Boar Sperm Cells Capacitation: Possible Involvement of HVA Calcium Channels

“…In summary, F3 produces an inhibition of the calcium current with partial recovery and no changes in the current kinetics. The effect of anemone venoms on ion channel activity has been documented in sodium [32,33] and potassium channels [34]. However, little is known about the effect of anemone venoms on calcium channels.…”