Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance

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 towards an adaptive peak of chemical defense.

Does batrachotoxin autoresistance coevolve with toxicity inPhyllobatespoison‐dart frogs?

“…For example, Tarvin et al. () recently found an important effect of the genetic background (poison frog vs human) when performing site‐directed mutagenesis tests of epibatidine resistance. Although substitutions S429A, I433V, and V1583I could presumably be involved in resistance to other alkaloids, they all occur at sites of demonstrated relevance in BTX binding to Na V 1.4 (Wang and Wang ; Vendantham and Cannon ) or Na V 1.5 (Wang et al.…”

“…Some of these changes have been shown to provide toxin resistance in vitro (Tarvin et al. ; Wang and Wang ).…”

“…Poison frogs of the family Dendrobatidae are a promising system to study the evolution of toxicity and autoresistance. The ability to sequester defensive alkaloids from dietary sources has evolved independently multiple times in this group (Santos et al 2003;Vences et al 2003;Santos and Cannatella 2011), and recent studies have identified amino acid substitutions on ion-transport proteins targeted by these toxins that coincide phylogenetically with the origins of alkaloid sequestration (Tarvin et al , 2017aYuan and Wang 2018). Some of these changes have been shown to provide toxin resistance in vitro (Tarvin et al 2017a;Wang and Wang 2017).…”

A tale of ligands big and small: An update on how pentameric ligand-gated ion channels interact with agonists and proteins

“…The alkaloids include the most potent of all α4β2 agonists, epibatidine. By sequencing the α4 and β2 genes in several genera, Tarvin and co-workers [47] identified a single Ser-to-Cys point mutation, which is present in all epibatidine-carrying frogs. This residue (Cys108) is located in a β sheet between loop A and loop E of the β2 subunit, in an area outside the binding site for ACh, which is much smaller than epibatidine.…”

Do not poison thyself

“…Some frogs underwent further amino changes in their nAChR receptor to restore the ability to bind acetylcholine, while still being insensitive to epibatidine, as researchers at the University of Texas in Austin, USA, showed [2]. The frogs first evolved toxicity by isolating chemicals from their arthropod prey and storing them in their skin.…”