Phyla- and subtype-selectivity of CgNa, a Na+ channel toxin from the venom of the Giant Caribbean Sea Anemone Condylactis gigantea

Because of their prominent role in electro-excitability, voltage gated sodium (Na-v) channels have become the foremost important target of animal toxins.These toxins have developed the ability to discriminate between closely related Na-v subtypes, making them powerful tools to study Na-v channel function and structure. CgNa is a 47-amino acid residue type I toxin isolated from the venom of the Giant Caribbean Sea Anemone Condylactis gigan tea. Previous studies showed that this toxin slows the fast inactivation of tetrodotoxin-sensitive Na-v currents in rat dorsal root ganglion neurons. To illuminate the underlying Na-v subtype-selectivity pattern, we have assayed the effects of CgNa on a broad range of mammalian isoforms (Na-v 1.2 Na-v 1.8) expressed in Xenopus oocytes. This study demonstrates that CgNa selectively slows the fast inactivation of rNa(v) 1.3/beta(1), mNa(v) 1.6/beta, and, to a lesser extent, hNa(v) 1.5/beta(1), while the other mammalian isoforms remain unaffected. Importantly, CgNa was also examined on the insect sodium channel DmNa(v)1/tipE, revealing a clear phyla-selectivity in the efficacious actions of the toxin. CgNa strongly inhibits the inactivation of the insect Na-v channel, resulting in a dramatic increase in peak current amplitude and complete removal of fast and steady-state inactivation. Together with the previously determined solution structure, the subtype-selective effects revealed in this study make of CgNa an interesting pharmacological probe to investigate the functional role of specific Na-v channel subtypes. Moreover, further structural studies could provide important information on the molecular mechanism of Na-v channel inactivation.