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Review
. 2020 Jan 22;8(3):259-271.
doi: 10.1016/j.gendis.2020.01.008. eCollection 2021 May.

Na,K-ATPase as a target for endogenous cardiotonic steroids: What's the evidence?

Sergei N Orlov  1   2   3 , Artem M Tverskoi  1 , Svetlana V Sidorenko  1   2 , Larisa V Smolyaninova  1   2 , Olga D Lopina  1 , Nickolai O Dulin  4 , Elizaveta A Klimanova  1   2
Affiliations
Review

Na,K-ATPase as a target for endogenous cardiotonic steroids: What's the evidence?

Sergei N Orlov et al. Genes Dis. .

Abstract

With an exception of few reports, the plasma concentration of ouabain and marinobufagenin, mostly studied cardiotonic steroids (CTS) assessed by immunoassay techniques, is less than 1 nM. During the last 3 decades, the implication of these endogenous CTS in the pathogenesis of hypertension and other volume-expanded disorders is widely disputed. The threshold for inhibition by CTS of human and rodent α1-Na,K-ATPase is ∼1 and 1000 nM, respectively, that rules out the functioning of endogenous CTS (ECTS) as natriuretic hormones and regulators of cell adhesion, cell-to-cell communication, gene transcription and translation, which are mediated by dissipation of the transmembrane gradients of monovalent cations. In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase, decrease the [Na+]i/[K+]i-ratio and increase cell proliferation. Possible physiological significance and mechanism of non-canonical Na+ i/K+ i-dependent and Na+ i/K+ i-independent cell responses to CTS are discussed.

Keywords: Cell proliferation; Cellular signaling; Endogenous cardiotonic steroids; Na+,K+-ATPase; Transcription; Translation.

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Figures

Figure 1
Figure 1
Structure of 4 cardiotonic steroids: cardenolides (ouabain and digoxin) having 5-membering lactone ring in 17-th position of steroid core; bufadienolides (marinobafagenin and bufalin) with 6-membering lactone ring in this position.
Figure 2
Figure 2
Plasma concentration of ECTS detected by immunoassay technique and dose-dependent cellular actions of ouabain in non-rodent mammalian cells. Activatory and inhibitory actions of ouabain are shown by red and blue, respectively. For original data, see text and Table 1, Table 2, Table 3
Figure 3
Figure 3
Effects of CTS binding to Na,K-ATPase: role of [Na+]i/[K+]i -ratio changes (increase and decrease) that are produced by Na,K-ATPase inhibition and activation, respectively, and triggering cell signaling due to Na,K-ATPase conformational changes and protein–protein interaction.
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