How poison dart frogs don't poison themselves

The little devil frog, Oophaga sylvatica, is one of the poison dart frog species in this study. Photo by Lucas Bustamante.

Poison dart frogs (frogs of the family Dendrobatidae, which as far as I can tell comes from "climbs trees" in Greek), are emblematic of the tropics. They are incredibly brightly colored, from blues to reds, to greens and yellows, in stripes as well as spots. But they are as well known for their poisons as for their colors. Their skins contain toxins such as epibatidine, a general toxin that can kill in doses as small as a microgram. They acquire these toxins from consuming poisonous insects (such as centipedes). Extracts from some species of poison dart frogs were used by indigenous Americans to poison the tips of their blow darts. But how does an animal as poisonous as a poison dart frog not poison itself?

This weeks paper, entitled "Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance" is lead-authored by postdoctoral researcher Rebecca Tarvin (UT Austin) and is in Science. Animals that acquire defensive toxins through their diet are generally thought to have three alternative paths available to them to not poison themselves. 1) They can compartmentalize the toxin in their tissues such that toxin is kept separate from the tissues that would be sensitive to it. 2)  They can metabolize the toxin to reduce its toxicity to themselves. 3) They can be insensitive to the toxin's effect. This third option sounds like the safest. There is a hitch, however, because the best toxins are ones with very general effects on many different potential predators. For a toxin to be effective it needs to bind to a receptor. So what types of receptors do many different, distantly related (birds AND rodents AND snakes for instance) all have? Ones that are crucial for biological function. Such is the case with the poison frog, as epibatidine binds to the receptors for acetylcholine, a widespread nerve signaling molecule (neurotransmitter). But how then does the poison frog cope? It needs to be insensitive to epibatidine but still be sensitive to acetylcholine. 

Tarvin and her colleagues found that in the two groups of poison dart frogs that both make epibatidine, they have a single amino acid substitution that changes an amino acid in their acetylcholine receptor, making them insensitive to epibatidine. Both groups separately evolved this same nucleotide change (millions of years apart!). This change alone would make the two groups also less sensitive to acetylcholine, but each group separately evolved a different secondary amino acid substitution that restores their sensitivity to acetylcholine. This highlights the myriad paths that evolution can travel, parts of the solution are reached by the same paths in different lineages, and other parts of solution are achieved through different paths. 

As molecular, biochemical, and neurophysiology techniques improve we are starting to find insights into how a trait as complicated as resistance to a general toxin can evolve, and this paper is a wonderful example of how exciting those discoveries can be.