Poisonous organisms carry small molecule toxins that alter voltage-gated sodium channel (Na✓) function. Among these, batrachotoxin (BTX) fromPitohuitoxic birds andPhyllobatespoison frogs, stands out because of its lethality and unusual effects on Navfunction. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NavDIVS6 pore-forming helix N→T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent fromPitohuiand poison frog Navs, incurs a strong cost that compromises channel function, and fails to produce BTX-resistant channels when tested in the context of poison frog Navs. We further show that captive-raised poison frogs are BTX resistant, even though they bear BTX-sensitive Navs. Hence, our data refute the hypothesis that BTX autoresistance is rooted in Navmutations and instead suggest that more generalizable mechanisms such as toxin sequestration act to protect BTX-bearing species from autointoxication.
