Research Article

Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance

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Science  22 Sep 2017:
Vol. 357, Issue 6357, pp. 1261-1266
DOI: 10.1126/science.aan5061

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Poison frogs resist their own chemical defense

Poison frogs sequester and store a neurotoxin that protects them from predation. The frogs, however, run the risk of intoxicating themselves. Studying the frog neurotoxin epibatidine, which binds to acetylcholine receptors, Tarvin et al. found a single amino acid substitution. The substitution changes the configuration of the acetylcholine receptor, so that it decreases its sensitivity to the toxin. But acetylcholine signaling is essential for normal life. Expressing poison frog and human receptors in frog eggs revealed that different amino acid substitutions have occurred in different lineages that allow the frog to resist its own toxins while still letting target neurotransmitters function effectively.

Science, this issue p. 1261

Abstract

Animals that wield toxins face self-intoxication. Poison frogs have a diverse arsenal of defensive alkaloids that target the nervous system. Among them is epibatidine, a nicotinic acetylcholine receptor (nAChR) agonist that is lethal at microgram doses. Epibatidine shares a highly conserved binding site with acetylcholine, making it difficult to evolve resistance yet maintain nAChR function. Electrophysiological assays of human and frog nAChR revealed that one amino acid replacement, which evolved three times in poison frogs, decreased epibatidine sensitivity but at a cost of acetylcholine sensitivity. However, receptor functionality was rescued by additional amino acid replacements that differed among poison frog lineages. Our results demonstrate how resistance to agonist toxins can evolve and that such genetic changes propel organisms toward an adaptive peak of chemical defense.

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