Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts

Abstract

Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na+ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na+i/K+i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death. It was also shown that CTS trigger diverse signaling cascades via conformational transitions of the Na+,K+-ATPase α-subunit that, in turn, results in the activation of membrane-associated non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase and the inositol 1,4,5-triphosphate receptor. These findings allowed researchers to propose that endogenous CTS might be considered as a novel class of steroid hormones. We focus our review on the analysis of the relative impact Na+i,K+i-mediated and -independent pathways in cellular responses evoked by CTS.

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

“…Convallatoxin-induced inhibition of viral protein translation by methionine transport reduction is not the only mechanism attributed to the antiviral activity of cardiac glycosides. Alternate mechanisms of action are based on the ability of these compounds to modulate cell signalling pathways [370]. For example, cardiac glycoside digitoxin has been reported to inhibit HCMV through induction of cellular autophagy following activation of the regulatory kinase AMPK via a novel NA + ,K + -ATPase subunit α1-AMPK-ULK1 pathway [173].…”

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

“…Importantly, while the current review has focused primarily on the non-ion dependent signaling mechanisms of the NKA, the [Na + ]i/[K + ]i ratio has been shown to also initiate similar signaling events. A number of important studies have shown the role of NKA inhibition and elevation of the [Na + ]i/[K + ]i ratio in the activation of Src-EGFR-MAPK- and Akt-mediated signaling pathways triggered by CTS, and readers are referred to a recent review which more thoroughly addresses this topic [ 83 ]. The importance of this concept is highlighted by recent data showing that NKA inhibition by CTS triggers TGFβ-induced fibrosis in cultured human lung fibroblasts via [Na + ]i/[K + ]i-mediated signaling which results in augmented expression of COX-2 [ 84 ] and downregulation of TGFβ2R [ 85 ].…”

Ouabain Suppresses IL-6/STAT3 Signaling and Promotes Cytokine Secretion in Cultured Skeletal Muscle Cells

“…An increase in [Na + ] i suppresses Ca 2+ extrusion via the Na + /Ca 2+ exchanger (NCX), thereby elevating intracellular Ca 2+ concentrations (Baker et al, 1969;Blaustein and Hamlyn, 2020;Pavlovic, 2020). An increase in [Na + ] i may also stimulate Na + -sensitive signaling pathways (Kuroki et al, 1997), while a decrease in [K + ] i suppresses protein translation (Orlov et al, 2017;Amarelle et al, 2019;Klimanova et al, 2019).…”