Poison frogs resist their own chemical defense Poison frogs produce 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 frog receptors in human cells 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 Poison frogs have evolved mutations in nicotinic acetylcholine receptor genes that confer toxin resistance. 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.

中文翻译：

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相互作用的氨基酸替代物使毒蛙进化出抗埃巴替丁

毒蛙抵抗自己的化学防御毒蛙会产生一种神经毒素，保护它们免受捕食。然而，青蛙冒着使自己陶醉的风险。Tarvin 等人研究了与乙酰胆碱受体结合的青蛙神经毒素依巴替丁。发现一个单一的氨基酸取代。这种取代改变了乙酰胆碱受体的构型，从而降低了它对毒素的敏感性。但乙酰胆碱信号对正常生活至关重要。在人类细胞中表达青蛙受体表明，不同谱系中发生了不同的氨基酸取代，使青蛙能够抵抗自身的毒素，同时仍然让目标神经递质有效发挥作用。科学，这个问题 p。1261 毒蛙进化出烟碱乙酰胆碱受体基因突变，赋予毒素抗性。使用毒素的动物面临自我中毒。毒蛙有多种针对神经系统的防御性生物碱。其中包括依巴替丁，一种烟碱型乙酰胆碱受体 (nAChR) 激动剂，在微克剂量下可致死。依巴替丁与乙酰胆碱共享一个高度保守的结合位点，使其难以进化出抗性但仍保持 nAChR 功能。人类和青蛙 nAChR 的电生理分析表明，一种氨基酸替代在毒蛙中进化了 3 倍，降低了表巴替丁的敏感性，但以乙酰胆碱敏感性为代价。然而，受体功能是通过在毒蛙谱系中不同的额外氨基酸替换来挽救的。