1. Academic Validation
  2. Ouabain-Induced Cell Death and Survival. Role of α1-Na,K-ATPase-Mediated Signaling and [Na+]i/[K+]i-Dependent Gene Expression

Ouabain-Induced Cell Death and Survival. Role of α1-Na,K-ATPase-Mediated Signaling and [Na+]i/[K+]i-Dependent Gene Expression

  • Front Physiol. 2020 Sep 4:11:1060. doi: 10.3389/fphys.2020.01060.
Olga Dmitrievna Lopina 1 Artem Mikhaylovich Tverskoi 2 3 Elizaveta Andreevna Klimanova 1 Svetlana Vadimovna Sidorenko 1 Sergei Nikolaevich Orlov 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • 2 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences (RAS), Moscow, Russia.
  • 3 Laboratory of Biological Membranes, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
Abstract

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+]i-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+]i/[K+]i 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.

Keywords

Na,K-ATPase; cardiotonic steroids; cell death; gene expression; intracellular Na+ and K+; intracellular signaling; ouabain.

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