Recent studies have revealed that Na/K-ATPase (NKA) can transmit signals through ion-pumping–independent activation of pathways relayed by distinct intracellular protein/lipid kinases, and endocytosis challenges the traditional definition that cardiotonic steroids (CTS) are NKA inhibitors. Although additional effects of CTS have long been suspected, revealing its agonist impact through the NKA receptor could be a novel mechanism in understanding the basic biology of NKA. In this study, we tested whether different structural CTS could trigger different sets of NKA/effector interactions, resulting in biased signaling responses without compromising ion-pumping capacity. Using purified NKA, we found that ouabain, digitoxigenin, and somalin cause comparable levels of NKA inhibition. However, although endogenous ouabain stimulates both protein kinases and NKA endocytosis, digitoxigenin and somalin bias to protein kinases and endocytosis, respectively, in LLC-PK1 cells. The positive inotropic effects of CTS are traditionally regarded as NKA inhibitors. However, CTS-induced signaling occurs at concentrations at least one order of magnitude lower than that of inotropy, which eliminates their well known toxic actions on the heart. The current study adds a novel mechanism that CTS could exert its biased signaling properties through the NKA signal transducer.

中文翻译：

---

强心类固醇对 Na/K-ATP 酶介导的信号转导的影响

最近的研究表明，Na/K-ATP 酶 (NKA) 可以通过不依赖离子泵的激活由不同的细胞内蛋白/脂质激酶传递的通路传递信号，并且内吞作用挑战了强心类固醇 (CTS) 是 NKA 抑制剂的传统定义。尽管长期以来一直怀疑 CTS 的其他作用，但通过 NKA 受体揭示其激动剂作用可能是了解 NKA 基础生物学的一种新机制。在这项研究中，我们测试了不同结构的 CTS 是否可以触发不同组的 NKA/效应器相互作用，从而在不影响离子泵送能力的情况下产生偏向的信号反应。使用纯化的 NKA，我们发现哇巴因、洋地黄毒苷和 somalin 导致 NKA 抑制水平相当。然而，尽管内源性哇巴因刺激蛋白激酶和 NKA 内吞作用，但在 LLC-PK1 细胞中，洋地黄毒苷和 somalin 分别偏向蛋白激酶和内吞作用。CTS 的正性肌力作用传统上被认为是 NKA 抑制剂。然而，CTS 诱导的信号发生的浓度至少比正性肌力低一个数量级，这消除了它们众所周知的对心脏的毒性作用。目前的研究增加了一种新的机制，即 CTS 可以通过 NKA 信号传感器发挥其偏向信号特性。CTS 诱导的信号发生的浓度至少比正性肌力低一个数量级，这消除了它们众所周知的对心脏的毒性作用。目前的研究增加了一种新的机制，即 CTS 可以通过 NKA 信号传感器发挥其偏向信号特性。CTS 诱导的信号发生的浓度至少比正性肌力低一个数量级，这消除了它们众所周知的对心脏的毒性作用。目前的研究增加了一种新的机制，即 CTS 可以通过 NKA 信号传感器发挥其偏向信号特性。