Na+/K+-ATPase Signaling in Health and Disease

The Na⁺/K⁺-ATPase is a ubiquitous P-type ion pump that actively exports three sodium ions in exchange for two potassium ions per ATP hydrolysed, thereby maintaining electrochemical gradients essential to cellular excitability, nutrient transport and volume regulation. Beyond its canonical pumping role, the enzyme serves as a versatile signalling scaffold: conformational changes induced by ligand binding or post-translational modification recruit kinases, adaptors and growth‐factor receptors to propagate cascades that regulate cell growth, differentiation and survival. Dysregulation of Na⁺/K⁺-ATPase signalling has emerged as a central feature in a spectrum of disorders. In the cardiovascular system, modest inhibition of the pump by endogenous ouabain-like factors or clinical cardiac glycosides triggers Src and MAPK pathways contributing to hypertrophy and arrhythmia. In the nervous system, mutations in α-subunit isoforms perturb pump kinetics and signalling interactions, leading to alternating hemiplegia, dystonia-parkinsonism and other neurodevelopmental syndromes. In cancer, Na⁺/K⁺-ATPase serves as a druggable receptor for cardiac glycosides that can initiate apoptosis and immunogenic cell death in tumour cells. Recent work has further linked perturbations in Na⁺ homeostasis to behavioural and metabolic phenotypes, underscoring the pump’s systemic importance. Advances elucidating isoform-specific regulation, non-pumping receptor pools and the molecular architecture of signalling complexes have refined our understanding of how Na⁺/K⁺-ATPase integrates ion transport with cellular communication to maintain health and, when misregulated, drive disease.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Na+/K+-ATPase Signaling in Health and Disease publication trend

The graph below shows the total number of articles in na+/k+-atpase signaling in health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Na⁺/K⁺-ATPase: A membrane-embedded P-type ATPase that exports Na⁺ and imports K⁺ to generate electrochemical gradients and act as a signal transducer.

Cardiac glycosides: Steroidal compounds that bind the Na⁺/K⁺-ATPase α-subunit, partially inhibiting ion transport and triggering intracellular signalling pathways.

FXYD proteins: Small single-pass membrane regulators that associate with Na⁺/K⁺-ATPase to modulate pump kinetics and signalosome assembly.

Isoform: A variant of a protein arising from different gene products or splicing, with distinct kinetic and regulatory properties.

Apoptotic machinery: The ordered network of caspases and regulatory factors that orchestrate programmed cell death.

References

1. Cardiac glycoside ouabain efficiently targets leukemic stem cell apoptotic machinery independent of cell differentiation status. Cell Communication and Signaling (2023).
2. The zebrafish mutant dreammist implicates sodium homeostasis in sleep regulation. eLife (2023).
3. The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. Frontiers in Physiology (2017).
4. Protein Interaction and Na/K-ATPase-Mediated Signal Transduction. Molecules (2017).
5. Anticancer and Immunogenic Properties of Cardiac Glycosides. Molecules (2017).
6. Involvement of Src and Epidermal Growth Factor Receptor in the Signal-transducing Function of Na+/K+-ATPase*. Journal of Biological Chemistry (2000).
7. Identification of a Pool of Non-pumping Na/K-ATPase*. Journal of Biological Chemistry (2007).
8. A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. Orphanet Journal of Rare Diseases (2014).
9. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood—a study of 155 patients. Orphanet Journal of Rare Diseases (2015).
10. Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. PLOS ONE (2015).