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

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.

Cardiac Glycosides as Immune System Modulators

“…The very complex cascade of NKA signalosome ( Figure 2 ), has been recently extensively reviewed elsewhere, see refs. [ 35 , 36 , 37 ]. In brief, after stimulation of NKA by CGs, protein tyrosine phosphorylation has been detected, though, NKA does not include a kinase domain.…”

The Effects of Short-Term Changes in Sodium Intake on Plasma Marinobufagenin Levels in Patients with Primary Salt-Sensitive and Salt-Insensitive Hypertension

“…These “humoral factors”, are endogenous cardiotonic steroids (CTS) similar to aglycone bufadienolides (such as marinobufagenin (MBG)) and cardienolides (such as ouabain) [ 19 ]. A number of α, β and γ NKA subunit isoforms have been described, which are expressed in a tissue-dependent manner and differ in terms of sensitivity to different CTS between species [ 20 , 21 ]. As was previously pointed out, the cardienolides have a predilection for the α2 and α3 isoforms which are expressed in vascular smooth muscle cells (VSMC), skeletal muscle, heart, central and peripheral nervous system.…”

Effect of Detergents on Activity and Magnesium-Dependent Properties of Different Isoforms of Na+,K+-ATPase in the Crude Membrane Fraction of Rat Cerebral Cortex

“…It should be borne in mind that these data (Fig. 2) are a result of manifestation of activity of several isoforms of the enzyme (α1, α2, and α3) that are simultaneously present in rat brain neurons [12,13,15]. Hence, these data are the integral result of the kinetics of all isoforms of the enzyme.…”

“…Therefore, changes in membrane properties caused by detergents can ultimately affect the kinetics of the enzyme and lead to misinterpretation of the obtained results. Neuronal membranes, in addition to relatively tolerant to ouabain α1-isoform of the enzyme, also contain ouabain-sensitive α2-and α3-isoforms [4,12] that differ from the α1 isoform by localization in membrane microdomains, and as a consequence, the composition of the lipid environment [15]. This suggests that when using detergents to identify the proper level of Na + ,K + -ATPase activity, it is necessary to be guided by a number of restrictions: not to use excessive concentrations of detergents, and also to take into account possible difference in the effect of the same detergents on the kinetics of different enzyme isoforms.…”