The strange reason why poisonous animals survive their own toxins

You don’t want to mess with the golden poison frog, aka the poison dart frog. Its cute appearance belies deadly physiology.

Just one of these tiny critters (scientific name: Phyllobates terribilis) contains enough toxins to kill 10 men, making them one of the most lethal animals on the planet relative to their size, which is not much bigger than a paperclip.

Since animals like the golden poison frog are so deadly, scientists have long wondered how their bodies can withstand their own toxins. We might finally have an answer to that question, and it reveals the surprisingly complex mechanisms animals adapt to survive.

The study results were published Thursday in the Journal of General Physiology.

How they did it — The University of California, San Francisco team wanted to better understand how animals like the golden poison frog and the Pitohui poison bird survive the toxins within their own bodies.

The Pitohui poison bird (Uropygialis meridionalis) lives in New Guinea, while the golden poison frog’s habitat is native to central and South America. These two animals stand out because of the lethal batrachotoxin found in their skin and feathers.

Batrachotoxin is a small molecule that alters the body’s sodium (Nav) channels. Sodium-ion channels help provide electrical signals to cells and are essential to the body’s physiology, dealing with everything from movement to brain function.

Previously, researchers thought that many poisonous animals survive their body’s toxins by developing protein mutations, which make their sodium channels resistant to the poison. But there are reasons to be skeptical of this scientific assumption, according to the researchers.

“[T]here haven’t been any functional studies of poison frog or Pitohui sodium channels, so whether batrachotoxin-bearing animals rely on changes within their sodium channels or alternative resistance mechanisms remains unclear,” Daniel L. Minor, Jr., a professor at UCSF’s Cardiovascular Research Institute and a co-author of the study, said in a press statement.

The researchers suspected that other unknown mechanisms might prevent Pitohui birds and golden poison frogs from poisoning themselves — a phenomenon known as auto-intoxication.

To test whether and how the animals developed resistance to batrachotoxin, the scientists cloned and analyzed copies of the Pitohui bird and golden poison frog’s sodium ion channels, testing how these channels responded to the poisonous batrachotoxin.

The golden poison dart frog contains poison that can kill 10 grown men, so how does it survive its own body? Scientists may have an answer to that question. Getty

What’s new — The researchers were surprised by their results, stating that “even though Pitohui carry [batrachotoxin] in their skeletal muscles and heart,” the sodium ion channels in these same parts of their body were still sensitive to the poison.

Golden poison frogs, which also secrete batrachotoxin, displayed similar sensitivity to the poison in their sodium ion channels.

In other words: even though the golden poison frog and the Pitohui bird were overall resistant to batrachotoxin, their sodium ion channels were still susceptible to the poison.

Therefore, the animals’ sodium channels couldn’t have developed a mutation that would provide resistance to batrachotoxin. The researchers concluded some other mechanism must be protecting the animals from the poison.

As the researchers continued testing the sodium ion channels, they realized that another toxin-binding protein, saxiphilin, could protect the frogs’ sodium ion channels from another poison known as saxitoxin. Scientists previously found that this protein can protect poisonous pufferfish from auto-intoxication.

The protein effectively acts as a “toxin sponge” by soaking up and storing the poison, protecting the frog from its own lethal toxins. The scientists concluded that this toxin sponge could also theoretically protect the animal from batrachotoxin and other poisons.

Birds in the Pitohui genus contain poisons in their feathers, but their own bodies are resistant to the toxins. Scientists may have figured out the answer to this lethal conundrum Getty

Why it matters — The researchers aren’t just one step closer to cracking the puzzle of the golden poison frog or the Pitohui bird. They’re also helping us better understand the evolutionary adaptations that animals undertake to survive in a harsh world.

Animals developed poison to defend themselves against predators, and, in turn, their bodies adapted to protect themselves from the toxins. But the exact bodily mechanisms that these birds and frogs adapted were previously unknown — until now.

The study’s findings highlight how science is a constantly evolving process. As our scientific methods develop, we can use our growing knowledge to better understand the fascinating, mysterious, and deadly adaptations of flora and fauna around us.

What’s next — While the researchers propose an intriguing mechanism, further research will be necessary to confirm the full potential of toxin sponges. The researchers haven’t yet identified any toxin sponges capable of binding to batrachotoxin, though their research suggests that these sponges are capable of binding to many different poisons.

Additional research may yield even more exciting insights that could extend into the human realm. Scientists suggest that this evolutionary sponge mechanism in frogs could help humans develop antidotes to protect themselves from lethal toxins.

“These […] strategies might not only offer a general means of toxin protection, but could also act in pathways involved in safely transporting and concentrating toxins in key defensive organs such as the skin,” Minor said.

Minor added, “Understanding these pathways may lead to the discovery of antidotes against various toxic agents.”

Abstract: Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX “toxin sponge” protein saxiphilin is able to protect and rescue NaVs from block by STX. 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.

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