The way poison frogs keep from poisoning themselves is complicated

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For some poison dart frogs, gaining resistance to one of their own toxins came with a price.

The genetic change that gives one group of frogs immunity to a particularly lethal toxin also disrupts a key chemical messenger in the brain. But the frogs have managed to sidestep the potentially damaging side effect through other genetic tweaks, researchers report in the Sept. 22 Science.

While other studies have identified genetic changes that give frogs resistance to particular toxins, this study “lets you look under the hood” to see the full effects of those changes and how the frogs are compensating, says Butch Brodie, an evolutionary biologist at the University of Virginia in Charlottesville who wasn’t involved in the research.

Many poison dart frogs carry cocktails of toxic alkaloid molecules in their skin as a defense against predators (SN Online: 3/24/14). These toxins, picked up through the frogs’ diets, vary by species. Here, researchers studied frogs that carry epibatidine, a substance so poisonous that just a few millionths of a gram can kill a mouse.

Previous studies have shown that poisonous frogs have become resistant to the toxins the amphibians carry by messing with the proteins that these toxins bind to in the body. Switching out certain protein building blocks, or amino acids, changes the shape of the protein, which can prevent toxins from latching on. But making that change could have unintended side effects, too, says study coauthor Rebecca Tarvin, an evolutionary biologist at the University of Texas at Austin.

For example, the toxin epibatidine binds to proteins that are usually targeted by acetylcholine, a chemical messenger that’s necessary for normal brain function. So Tarvin and her colleagues looked at how this acetylcholine receptor protein differed between poison frog species that are resistant to epibatidine and some of their close relatives that aren’t.

Identifying differences between the frogs in the receptor protein’s amino acids allowed researchers to systematically test the effects of each change. To do so, the scientists put the genetic instructions for the same protein in humans, who aren’t resistant to epibatidine, into frog eggs. The researchers then replaced select amino acids in the human code with different poison frog substitutions to find an amino acid “switch” that would make the resulting receptor protein resistant to epibatidine.

But epibatidine resistance wasn’t a straightforward deal, it turned out. “We noticed that replacing one of those amino acids in the human [protein] made it resistant to epibatidine, but also affected its interaction with acetylcholine,” says study coauthor Cecilia Borghese, a neuropharmacologist also at the University of Texas at Austin. “Both are binding in the exact same region of the protein. It’s a very delicate situation.” That is, the amino acid change that made the receptor protein resistant to epibatidine also made it harder for acetylcholine to attach, potentially impeding the chemical messenger’s ability to do its job.

But the frogs themselves don’t seem impaired. That’s because other amino acid replacements elsewhere in the receptor protein appear to have compensated, Borghese and Tarvin found, creating a protein that won’t let the toxin latch on, but that still responds normally to acetylcholine.

The resistance-giving amino acid change appears to have evolved three separate times in poison frogs, Tarvin says. Three different lineages of the frogs have resistance to the poison, and all of them got that immunity by flipping the same switch. But the amino acid changes that bring back a normal acetylcholine response aren’t the same across those three groups.

“It’s a cool convergence that these other switches weren’t identical, but they all seem to recover that function,” Brodie says.