Why Poison Frogs Don’t Poison Themselves

By Amanda Jiang ’21

A picture of the poison frog, Epipedobates anthonyi, seen in Germany (Source: Wikimedia Commons, by H. Krisp).

A picture of the poison frog, Epipedobates anthonyi, seen in Germany (Source: Wikimedia Commons, by H. Krisp).

Summary: Researchers at the University of Texas at Austin have recently discovered how the specific epibatidine toxin receptor interacts with epibatidine through studying its presence in Epipedobates anthonyi frogs. The epibatidine receptor has been found to be in the same receptor class as the pain and nicotine receptors in humans, so understanding how mutations in the epibatidine receptor prevents Epipedobates anthonyi frogs from being affected by their own poison may help researchers design better drugs to address pain and nicotine addiction.

Although colorful and cute in appearance, the Epipedobates anthonyi frog actually produces a dangerous toxin known as epibatidine. Epibatidine is toxic due to its ability to interact with nicotinic and pain receptors in the nervous system, interfering with sensation and movement. If animals are exposed to too much epibatidine, numbness and paralysis may result. 1 The Epipedobates anthonyi frog uses epibatidine to keep predators from eating them.

In poisoned animals, epibatidine works by binding to nicotinic receptors, inhibiting \, preventing smooth bodily movement, and eventually resulting in seizures and spasms. Such damage to the nervous system can kill animals as respiratory and circulatory functions are disrupted. Thus, the question of how these frogs can endure such potent poison in their bodies has been under investigation for years.

How exactly does the epibatidine receptor work? Rebecca Tarvin and her colleagues at the University of Texas at Austin found that like normal receptors, the epibatidine receptor  in these frogs only functions when a specific compound comes into contact with it. The toxin epibatidine can also bind the receptor, triggering a burst of activity that can be very dangerous.

Recently, researchers at the University of Texas at Austin have discovered that there is a mutation in these frogs’ DNA that prevents the toxin from acting. After looking at three different groups of frogs which use epibatidine, it was found that the genetic material of every group contained a particular mutation in just 3 of the 2,500 amino acids that code for the toxin receptor. This mutation results in epibatidine being unable to bind; furthermore, the normal substrate of the epibatidine receptor is more specialized and binds more selectively, resulting in more controlled levels of activity.

Due to its pain receptor-blocking quality, epibatidine has the potential to be used as a painkiller; however, its use was dismissed due to serious side effects including seizures and death 2 . However, because epibatidine also binds to pain and nicotine receptors, scientists can design similar molecules to block pain or nicotine addiction by using these frogs and studying their receptor mutation.

Scientists such as Cecilia Borghese, a research associate in the university’s Waggoner Center for Alcohol and Addiction Research, believe that “every bit of information we can gather on how these receptors are interacting with the drugs gets us a step closer to designing better drugs” 3 .

The changes in receptor that prevent the toxin from binding are not necessarily in the receptor’s active site. “The most exciting thing is how these amino acids that are not even in direct contact with the drug can modify the function of the receptor in such a precise way,” Borghese said. The healthy compound, she continued, “keeps working as usual, no problem at all, and now the receptor is resistant to epibatidine. That for me was fascinating.” 3

With this groundbreaking discovery, researchers are one step closer to finding out how to best use epibatidine as a therapeutic drug. In the future, epibatidine-like molecules may be used to prevent pain and treat nicotine addiction.

References:

  1. Fisher M, Huangfu D, Shen TY, Guyenet PG (1994).  “Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent.” . J Pharmacol Exp Ther.
  2. Science News Staff. “Painkiller From Frog’s Poison.” Science | AAAS, Science Magazine, 2 Jan. 1998, www.sciencemag.org/news/1998/01/painkiller-frogs-poison.
  3. University of Texas at Austin. “Why poison frogs don’t poison themselves.” ScienceDaily. ScienceDaily, 21 September 2017. <www.sciencedaily.com/releases/2017/09/170921141238.htm>.
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