Animal toxins that are used to subdue prey and deter predators act as the key drivers
in natural food chains and ecosystems. However, the predators of venomous animals
may exploit feeding adaptation strategies to overcome toxins their prey produce. Much
remains unknown about the genetic and molecular game process in the toxin-dominant
food chain model. Here, we show an evolutionary strategy in different trophic levels
of scorpion-eating amphibians, scorpions and insects, representing each predation
relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions
preying on insects, we found that the scorpion alpha-toxins irreversibly activate
the skeletal muscle sodium channel of their prey (insect, BgNa(V)1) through a membrane
delivery mechanism and an efficient binding with the Asp/Lys-Tyr motif of BgNa(V)1.
However, in the predatory game between frogs and scorpions, with a single point mutation
(Lys to Glu) in this motif of the frog's skeletal muscle sodium channel (fNa(V)1.4),
fNa(V)1.4 breaks this interaction and diminishes muscular toxicity to the frog; thus,
frogs can regularly prey on scorpions without showing paralysis. Interestingly, this
molecular strategy also has been employed by some other scorpion-eating amphibians,
especially anurans. In contrast to these amphibians, the Asp/Lys-Tyr motifs are structurally
and functionally conserved in other animals that do not prey on scorpions. Together,
our findings elucidate the protein-protein interacting mechanism of a toxin-dominant
predator-prey system, implying the evolutionary game theory at a molecular level.
