Lopina Olga Dmitrievna, Tverskoi Artem Mikhaylovich, Klimanova Elizaveta Andreevna, Sidorenko Svetlana Vadimovna, Orlov Sergei Nikolaevich
Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences (RAS), Moscow, Russia.
Front Physiol. 2020 Sep 4;11:1060. doi: 10.3389/fphys.2020.01060. eCollection 2020.
Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific inhibitors of Na,K-ATPase, the enzyme, which pumps Na and K across plasma membrane of animal cells. Treatment of cells by CTS affects various cellular functions connected with the maintenance of the transmembrane gradient of Na and K. Numerous studies demonstrated that binding of CTS to Na,K-ATPase not only suppresses its activity but also induces some signal pathways. This review is focused on different mechanisms of two ouabain effects: their ability (1) to protect rodent cells from apoptosis through the expression of [Na]-sensitive genes and (2) to trigger death of non-rodents cells (so-called «oncosis»), possessing combined markers of «classic» necrosis and «classic» apoptosis. Detailed study of oncosis demonstrated that the elevation of the [Na]/[K] ratio is not a sufficient for its triggering. Non-rodent cell death is determined by the characteristic property of "sensitive" to ouabain α1-subunit of Na,K-ATPase. In this case, ouabain binding leads to enzyme conformational changes triggering the activation of p38 mitogen-activated protein kinases (MAPK) signaling. The survival of rodent cells with ouabain-«resistant» α1-subunit is connected with another conformational transition induced by ouabain binding that results in the activation of ERK 1/2 signaling pathway.
哇巴因属于强心甾体（CTS）家族，是植物来源的化合物，多年来一直作为治疗剂和细胞毒性剂为人所知。它们是Na，K - ATP酶的特异性抑制剂，该酶负责将Na和K泵过动物细胞的质膜。用CTS处理细胞会影响与维持Na和K跨膜梯度相关的各种细胞功能。大量研究表明，CTS与Na，K - ATP酶的结合不仅会抑制其活性，还会诱导一些信号通路。这篇综述聚焦于哇巴因两种作用的不同机制：它们（1）通过[Na]敏感基因的表达保护啮齿动物细胞免于凋亡的能力，以及（2）触发非啮齿动物细胞死亡（所谓的“胀亡”）的能力，胀亡具有“经典”坏死和“经典”凋亡的综合标志物。对胀亡的详细研究表明，[Na]/[K]比值的升高不足以触发胀亡。非啮齿动物细胞死亡由对哇巴因“敏感”的Na，K - ATP酶α1亚基的特性决定。在这种情况下，哇巴因结合导致酶构象变化，触发p38丝裂原活化蛋白激酶（MAPK）信号通路的激活。具有哇巴因“抗性”α1亚基的啮齿动物细胞的存活与哇巴因结合诱导的另一种构象转变有关，这种转变导致ERK 1/2信号通路的激活。
