Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs
Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs
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钠通道中的趋同取代表明毒蛙毒素抗性的多个起源
DOI：
10.1093/molbev/msv350
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发表时间：
2016
影响因子：
10.7
通讯作者：
Cannatella, David C.
中科院分区：
文献类型：
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作者：
Tarvin, Rebecca D.;Santos, Juan C.;O'Connell, Lauren A.;Zakon, Harold H.;Cannatella, David C.
复杂的表型通常具有相应的多方面遗传成分。然而，化学防御和抗性之间的基因型-表型关联通常很简单：毒素结合位点的遗传变化改变了它影响靶标的方式。一些有毒生物，如毒蛙（无尾目：树蛙科），具有破坏离子通道功能的防御性生物碱，离子通道是神经和肌肉活动至关重要的蛋白质。使用蛋白质对接模型，我们预测，三个主要类别的毒蛙生物碱（histrionicotoxins，pumiliotoxins和batrachotoxins）结合到类似的网站在高度保守的肌肉电压门控钠通道，Nav1.4的内孔。我们预测，毒蛙对这些化合物有一定的抵抗力，因为它们在Nav1.4内孔中有六种类型的氨基酸替换，除了来自马达加斯加的远亲蜘蛛防御青蛙Mantella aurantiaca之外，所有其他青蛙都没有。蛋白质对接模型和比较遗传学支持这些替代在生物碱抗性中的作用。考虑到四个独立的化学防御的起源，在树蛙科，氨基酸取代的系统发育模式表明，1）生物碱抗性在Nav1.4独立进化至少5倍，在这些青蛙，2）抗性赋予的替代变化可能是不同物种的生物碱暴露的差异的结果，3）功能制约决定了Nav1.4内孔的演化。我们的研究是第一个证明在青蛙与生物碱防御自身抗性的遗传基础。
Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype–phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar,Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least five times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the first to demonstrate the genetic basis of autoresistance in frogs with alkaloid defenses.