Na+/K+-ATPase: More than an Electrogenic Pump

Abstract

The sodium pump, or Na⁺/K⁺-ATPase (NKA), is an essential enzyme found in the plasma membrane of all animal cells. Its primary role is to transport sodium (Na⁺) and potassium (K⁺) ions across the cell membrane, using energy from ATP hydrolysis. This transport creates and maintains an electrochemical gradient, which is crucial for various cellular processes, including cell volume regulation, electrical excitability, and secondary active transport. Although the role of NKA as a pump was discovered and demonstrated several decades ago, it remains the subject of intense research. Current studies aim to delve deeper into several aspects of this molecular entity, such as describing its structure and mode of operation in atomic detail, understanding its molecular and functional diversity, and examining the consequences of its malfunction due to structural alterations. Additionally, researchers are investigating the effects of various substances that amplify or decrease its pumping activity. Beyond its role as a pump, growing evidence indicates that in various cell types, NKA also functions as a receptor for cardiac glycosides like ouabain. This receptor activity triggers the activation of various signaling pathways, producing significant morphological and physiological effects. In this report, we present the results of a comprehensive review of the most outstanding studies of the past five years. We highlight the progress made regarding this new concept of NKA and the various cardiac glycosides that influence it. Furthermore, we emphasize NKA's role in epithelial physiology, particularly its function as a receptor for cardiac glycosides that trigger intracellular signals regulating cell-cell contacts, proliferation, differentiation, and adhesion. We also analyze the role of NKA β-subunits as cell adhesion molecules in glia and epithelial cells.

Keywords: Na+/K+-ATPase; cardiac glycosides; epithelia; ion pump; receptor; signalosome.

Figure 1

Structure and function of NKA pump. (A) The diagram depicts the conformational changes of various domains within the α subunit of NKA, along with the associated ligands for each transition. The red circled arrow denotes the physiological progression of the Post-Alberts cycle. (B) Representative crystal images demonstrate structural disparities between the two primary stages, E1 and E2 (created from PB IDs 3WGV and 7WYT [78,79]). (C) The topological profile of the α subunit is depicted to highlight its intracellular domains: actuator (A), nucleotide binding (N), and phosphorylation (P) domains.

Figure 2

Cardiac glycosides. The figure illustrates the basic chemical structure of CGs, comprising a steroid group with attached sugar and lactone groups, with each containing either five or six carbons. Additionally, it highlights the origins of notable CGs, such as ouabain, digoxin, and marinobufagenin.

Figure 3

Different signaling pathways activated by the binding of CGs and ROS to NKS. (A) The diagram depicts several signaling pathways, including the positive inotropic effect shown in the left inset, as well as those activated by SRC and PI3K transactivation within caveolae. Each signaling pathway is represented by arrows of varying colors. Additionally, the diagram includes the representation of the ROS amplification loop. (B) The diagram illustrates the generation of intracellular calcium oscillations and the involvement of molecular components, such as IP3R, ORAi1, and STIM1, along with voltage-dependent calcium channels (VDCCs). Arrows indicate the pathways. The “X” on NCX and NKA indicate diminished activity.

Figure 4

Ouabain–NKA-induced changes in epithelial cultured cells MDCK. The figure outlines the diverse signaling pathways triggered by the binding of ouabain, at nanomolar concentrations, to NKA. It illustrates the resulting effects on cellular components, including voltage-dependent potassium ion channels (VDKC) and TRPV4 channels, as well as the acceleration of ciliogenesis.