Abstract

The Na+,K+-ATPase (NKA), historically recognized as the primary ion transporter responsible for maintaining cellular Na+ and K+ gradients, is increasingly understood to be a **polyfunctional protein** with critical roles extending beyond ion homeostasis. This review comprehensively analyzes the emerging non-canonical functions of NKA, positioning it as a central component in cell signaling and membrane organization. The objective is to synthesize evidence demonstrating NKA's dual nature: an ion pump and a signal transducer. Our analysis highlights that NKA, particularly the α1 subunit, acts as a high-affinity receptor for cardiotonic steroids (CTS), which, upon binding, initiates a cascade of intracellular signaling pathways, including the activation of Src kinase and the modulation of reactive oxygen species (ROS) production. Furthermore, NKA functions as a scaffolding protein, forming supramolecular complexes with various regulatory and structural proteins at the plasma membrane, thereby influencing cell adhesion, migration, proliferation, and apoptosis. These findings underscore a paradigm shift in NKA research, revealing its integral role in cellular communication and pathophysiology. The study concludes that understanding NKA's polyfunctional capacity is essential for developing targeted therapeutic strategies for diseases such as heart failure, cancer, and neurodegeneration.