Saxiphilin functions as a "toxin sponge" protein that counteracts the effects of saxitoxin poisoning

Saxitoxin (STX) is among the most potent toxins known, is classified as a chemical weapon, and is the archetype of the paralytic shellfish toxin (PST) family produced by marine and freshwater harmful algal blooms (HAB)1-3. STX causes paralysis and death through inhibition of voltage gated sodium channels (NaVs), has no antidote, and poses a public health and commercial fishing threat due to its accumulation in seafood and increasing HAB occurrences1,4. Although STX is lethal to varied vertebrates5-7, including humans4,8,9, certain frogs resist STX poisoning6,7. This phenotype is thought to depend on soluble "toxin sponge" high-affinity STX binding proteins (saxiphilins, Sxphs)6,7,10,11 that provide resistance through a competition mechanism different from classic "target site" ion channel mutation mechanisms12-14. Here, we test this idea directly and show that a single dose of American bullfrog (Rana catesbeiana) Sxph (RcSxph) is sufficient to counteract STX neurotoxicity and lethality in mice using paradigms where STX and Sxph are administered together or sequentially in either order. Importantly, this function requires the RcSxph high-affinity STX binding site. Our findings provide in vivo validation that Sxphs are "toxin sponges" that protect against STX poisoning and highlight the potential to harness this protein class as antidotes for PSTs and other toxins.