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Review
. 2018 Sep 1;19(9):2600.
doi: 10.3390/ijms19092600.

The Na/K-ATPase Signaling: From Specific Ligands to General Reactive Oxygen Species

Rebecca D Pratt  1 , Cameron R Brickman  2 , Cameron L Cottrill  3 , Joseph I Shapiro  4 , Jiang Liu  5
Affiliations
Review

The Na/K-ATPase Signaling: From Specific Ligands to General Reactive Oxygen Species

Rebecca D Pratt et al. Int J Mol Sci. .

Abstract

The signaling function of the Na/K-ATPase has been established for 20 years and is widely accepted in the field, with many excellent reports and reviews not cited here. Even though there is debate about the underlying mechanism, the signaling function is unquestioned. This short review looks back at the evolution of Na/K-ATPase signaling, from stimulation by cardiotonic steroids (also known as digitalis-like substances) as specific ligands to stimulation by reactive oxygen species (ROS) in general. The interplay of cardiotonic steroids and ROS in Na/K-ATPase signaling forms a positive-feedback oxidant amplification loop that has been implicated in some pathophysiological conditions.

Keywords: Na/K-ATPase; ROS; Src. endocytosis; potassium; signaling; sodium.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
A schematic illustration of action of pNaKtide: Under control state, c-Src SH2 domain binds to α1 CD2 segment (indicated by arrow 1) and c-Src KD binds to α1 ND1 (indicated by arrow 2), which keeps c-Src inactive. Upon ouabain binding to the α1 subunit, the α1 subunit favors E-2P conformational status and c-Src KD released from α1 subunit that leads to phosphorylation of Tyr418 in c-Src KD. NaKtide and pNaKtide are derived from 20 aa (Ser415-Gln434) in α1 ND1, which can bind to the c-Src KD for the competitive binding of α1 ND1 and KD, thus preventing phosphorylation of Tyr418 in c-Src KD. In the illustration, ouabain is used as a representative of cardiotonic steroids. SH2, c-Src SH2 domain; KD, c-Src kinase domain; CD2, α1 subunit CD2 segment; ND1, α1 subunit ND1 segment.
Figure 2
Figure 2
Schematic illustration of different working models. In the illustration, ouabain is used as a representative of cardiotonic steroids. (A) The model of Na/K-ATPase/c-Src (binding) receptor complex. Binding between c-Src SH2 domain and α1 CD2 segment as well as c-Src KD domain and α1 ND1 segment are indicated by arrow 1 and 2, respectively. (B) the model of c-Src activation by transiently binding to Na/K-ATPase/Cav-1 complex; (C) the model of c-Src activation regulated by the ATP/ADP ratio, ATPase inhibitor vanadate, and low concentrations of Na+ and K+. In this model, there is no binding between Na/K-ATPase and c-Src. The role of Cav-1 was not tested. Please refer to the references for details. Cav-1, caveolin-1; ROS, reactive oxygen species.
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