Cardiotonic steroids (CTS) are a group of compounds known to be toxic due to their ability to inhibit the Na⁺/K⁺-ATPase (NKA), which is essential to maintain the balance of ions in animal cells. An evolutionary strategy of molecular adaptation to avoid self-intoxication acquired by CTS defended organisms and their predators is the structural modification of their NKA where specific amino acid substitutions confer resistant phenotypes. Several lineages of poison dart frogs (Dendrobatidae) are well known to sequester a wide variety of lipophilic alkaloids from their arthropod diet, however there is no evidence of CTS-sequestration or dietary exposure. Interestingly this study identified the presence of α-NKA isoforms (α₁ and α₂) with amino acid substitutions indicative of CTS-resistant phenotypes in skeletal muscle transcriptomes obtained from six species of dendrobatids: Phyllobates aurotaenia, Oophaga anchicayensis, Epipedobates boulengeri, Andinobates bombetes, Andinobates minutus, and Leucostethus brachistriatus, collected in the Valle del Cauca (Colombia). P. aurotaenia, A. minutus, and E. boulengeri presented two variants for α₁-NKA, with one of them having these substitutions. In contrast, O. anchicayensis and A. bombetes have only one α₁-NKA isoform with an amino acid sequence indicative of CTS susceptibility and an α₂-NKA with one substitution that could confer a reduced affinity for CTS. The α₁ and α₂ isoforms of L. brachistriatus do not contain substitutions imparting CTS resistance. Our findings indicate that poison dart frogs express α-NKA isoforms with different affinities for CTS and the pattern of this expression might be influenced by factors related to evolutionary, physiological, ecological, and geographical burdens.

强心类固醇 (CTS) 是一组已知有毒的化合物，因为它们能够抑制 Na ⁺ /K ⁺ -ATP 酶 (NKA)，而 NKA 对于维持动物细胞中的离子平衡至关重要。为了避免 CTS 防御生物体及其捕食者获得自我中毒，分子适应的进化策略是对其 NKA 进行结构修饰，其中特定的氨基酸取代赋予抗性表型。众所周知，箭毒蛙 (Dendrobatidae) 的几个谱系可以从节肢动物的饮食中隔离多种亲脂性生物碱，但是没有证据表明 CTS 隔离或饮食暴露。有趣的是，这项研究确定了 α-NKA 亚型（α ₁和 α ₂) 具有表明骨骼肌转录组中 CTS 抗性表型的氨基酸替换，这些转录组来自六种树蛙：Phyllobates aurotaenia、Oophaga anchicayensis、Epipedobates boulengeri、Andinobates bombetes、Andinobates minutus和Leucostethus brachistriatus，收集于 Valle del Cauca（哥伦比亚） . P. aurotaenia、A. minutus和E. boulengeri展示了 α ₁ -NKA 的两种变体，其中一种具有这些取代。相反，O. anchicayensis和A. bombetes只有一个 α₁ -NKA 同种型具有指示 CTS 易感性的氨基酸序列和具有一个替代的 α ₂ -NKA，可降低对 CTS 的亲和力。L. brachistriatus的α ₁和 α ₂亚型不包含赋予 CTS 抗性的取代。我们的研究结果表明，箭毒蛙表达对 CTS 具有不同亲和力的 α-NKA 亚型，这种表达模式可能受到与进化、生理、生态和地理负担相关的因素的影响。