Mending Fences: Na,K-ATPase signaling via Ca2+ in the maintenance of epithelium integrity

[Display omitted] •Na,K-ATPase is an ion pump and a signal transducer.•The Na,K-ATPase ligand, ouabain, activates an oscillatory Ca2+ signal in epithelial cells.•Ouabain/Na,K-ATPase induced Ca2+ oscillations activates a large scale signaling network.•Ouabain/Na,K-ATPase induced Ca2+ oscillations con...

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Bibliographic Details
Published inCell calcium (Edinburgh) Vol. 88; p. 102210
Main Authors Aperia, Anita, Brismar, Hjalmar, Uhlén, Per
Format Journal Article
LanguageEnglish
Published Elsevier Ltd 01.06.2020
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Summary:[Display omitted] •Na,K-ATPase is an ion pump and a signal transducer.•The Na,K-ATPase ligand, ouabain, activates an oscillatory Ca2+ signal in epithelial cells.•Ouabain/Na,K-ATPase induced Ca2+ oscillations activates a large scale signaling network.•Ouabain/Na,K-ATPase induced Ca2+ oscillations control cell adhesion and proliferation.•Ouabain/Na,K-ATPase induced Ca2+ oscillations protect from apoptosis.•Ouabain/Na,K-ATPase induced Ca2+ oscillations regulate STIM via phosphorylation. Na,K-ATPase is a ubiquitous multifunctional protein that acts both as an ion pump and as a signal transducer. The signaling function is activated by ouabain in non-toxic concentrations. In epithelial cells the ouabain-bound Na,K-ATPase connects with the inositol 1,4,5-trisphosphate receptor via a short linear motif to activate low frequency Ca2+ oscillations. Within a couple of minutes this ouabain mediated signal has resulted in phosphorylation or dephosphorylation of 2580 phospho-sites. Proteins that control cell proliferation and cell adhesion and calmodulin regulated proteins are enriched among the ouabain phosphor-regulated proteins. The inositol 1,4,5-trisphosphate receptor and the stromal interaction molecule, which are both essential for the initiation of Ca2+ oscillations, belong to the ouabain phosphor-regulated proteins. Downstream effects of the ouabain-evoked Ca2+ signal in epithelial cells include interference with the intrinsic mitochondrial apoptotic process and stimulation of embryonic growth processes. The dual function of Na,K-ATPase as an ion pump and a signal transducer is now well established and evaluation of the physiological and pathophysiological consequences of this universal signal emerges as an urgent topic for future studies.
ISSN:0143-4160
1532-1991
1532-1991
DOI:10.1016/j.ceca.2020.102210