Voltage-Gated Sodium Channel Substitutions Underlying Tetrodotoxin Resistance in Nemerteans: Ecological and Evolutionary Implications

Tetrodotoxin (TTX) is an extremely potent neurotoxin, a selective blocker of voltage-gated sodium (NaV) channels, produced by bacteria and accumulated across a wide range of taxa. Several TTX-bearing animals have developed molecular adaptations in their NaV channels that provide TTX resistance, making this toxin one of the factors of molecular evolution. However, the molecular basis of TTX resistance in NaV channels of a significant proportion of tetrodotoxic species remains poorly studied. Nemertea is a phylum of marine worms, comprising both TTX-bearing and non-TTX-bearing species. Here, we analyzed the amino acid sequences of the NaV1 channel regions responsible for TTX binding from 22 species of nemerteans. Substitutions previously characterized as conferring TTX resistance in other taxa were detected in sixteen nemerteans; local clustering was observed within several families. These findings suggest that TTX resistance in nemerteans evolved multiple times independently and may serve as either as an adaptation facilitating TTX accumulation for subsequent use for defense and predation, or as a mechanism allowing consumption of tetrodotoxic prey without toxin accumulation.