Equinatoxin II: How a Cationic Pore-Forming Sea Anemone Toxin Drives Nodal Swelling of Myelinated Nerve Fibers

This study was performed to elucidate the mechanism underpinning the nodal swelling induced by equinatoxin II (EqtII), a cation-selective pore-forming toxin derived from the sea anemone Actinia equina. Experiments were conducted using frog myelinated nerve fibers as a model system. Application of EqtII led to an approximately two-fold increase in the nodal volume of myelinated axons, but only when extracellular Ca²⁺ was present. Replacing extracellular Cl^- with isethionate had no measurable effect on this response, whereas substitution of NaCl with either sucrose or LiCl, an established Na⁺/Ca²⁺ exchanger (NCX) inhibitor, abolished the swelling. The persistence of the effect in the presence of tetrodotoxin indicates that voltage-gated Na⁺ channels are not involved in the underlying mechanism. Our data suggest that Ca²⁺ influx through EqtII-induced membrane pores raises intracellular Ca²⁺ levels, thereby stimulating the NCX in its forward-operating mode. This process promotes Ca²⁺ extrusion in exchange for Na⁺ entry. The resulting accumulation of intracellular Na⁺ increases osmotic pressure within the axon, leading to water influx and nodal swelling.