How vertebrates that bear BTX or other small-molecule toxins avoid autointoxication remains unresolved ( Arbuckle et al., 2017 Almabruk et al., 2018 Hunter, 2018). This lipophilic, steroidal neurotoxin is thought to bind in the Na V inner pore ( Wang and Wang, 2003). and Ifrita kowaldi Dumbacher et al., 1992 Dumbacher et al., 2000) and neotropical poison frogs ( Phyllobates Santos et al., 2016), stands out because of its lethality and its unusual ability to facilitate opening and prevent inactivation of voltage-gated sodium channels (Na Vs Catterall, 1977 Khodorov, 1985 Logan et al., 2016 Wang and Wang, 2003). Among these, batrachotoxin (BTX), a diet-acquired ( Daly et al., 1994b Daly et al., 1994a Dumbacher et al., 2004) steroidal amine found in distantly related vertebrate lineages, including poisonous birds ( Pitohui spp. Many organisms harbor various small-molecule toxins that target ion channels as a means of defense from predation ( Savitzky et al., 2012). Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins. Moreover, we demonstrate that the amphibian STX “toxin sponge” protein saxiphilin is able to protect and rescue Na Vs from block by STX. We also show that captivity-raised poison frogs are resistant to two Na V-directed toxins, BTX and saxitoxin (STX), even though they bear Na Vs sensitive to both. Here, we show that this variant is absent from Pitohui and poison frog Na Vs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog Na Vs. In poison frogs, a Na V DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. How these toxin-bearing organisms avoid autointoxication remains poorly understood. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on Na V function. Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (Na V) function.
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