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The Na, K-ATPase in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 8053

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Dr. Liora Shoshani

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Department of Physiology Biophysics and Neurosciences, Center for Research and Advanced Studies, CINVESTAV-IPN, Mexico City 07360, Mexico
Interests: Na⁺/K⁺-ATPase; β2/AMOG; β1-subunit; cell–cell interaction; protein–protein interaction
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Dear Colleagues,

The Na⁺,K⁺-ATPase, known as the Na⁺-pump, has been studied intensively, for nearly 70 years. Nonetheless, it is still at the center of interest for various disciplines. The central role of the pump is related to the exchange of Na⁺ and K⁺, at the expense of the hydrolysis of ATP, an activity realized by the α subunit. Nevertheless, the accessory subunits, β and γ, play an important role in this function. Initially, the role of the three isoforms of the β subunit of animal Na⁺/K⁺-ATPases has been shown to support protein folding and stability and to serve a role in occluding bound K⁺. Both old and emerging information at the molecular level strongly suggest that at least two isoforms of the β-subunit function such as cell-adhesion molecules in epithelia (β1) and as an adhesion molecule on the plasma membrane of astrocytes (β2/AMOG). The γ subunit (FXYD2) belongs to the family of regulatory proteins known as FXYD proteins. In mammals, there are seven members of this family, which are characterized by their small size (66–178 amino acids) and contain the sequence signature FXYD (PFXYD in mammals). These auxiliary subunits have been demonstrated to modulate kinetic properties and enhance enzyme stability within the membrane, with effects that vary depending on the tissue and isoform. While the direct impact on substrate affinities or Vmax values for Na,K-ATPase activity is modest, FXYDs may serve to finely adjust ion transport within specific organs or tissues.

In this Special Issue, our aim is to publish research and review articles describing current knowledge and data on the structure–function relationship of the Na⁺-pump in health and diseases. We are looking for articles that explore the roles played by α, β, and γ subunits at the molecular, biochemical, physiological, pharmacological, and genetic levels and how they impact the development, normal structure and function, and pathology of different tissues and organisms.

The scope of the Special Issue includes, but is not limited to, the following topics:

The structure of α, β, and γ subunits as components of the Na,K-ATPase.
The role of the different subunits in modulating the ion transport of Na,K-ATPase.
The adhesive properties of β-subunits in epithelia and nervous system.
The role of α, β, and γ subunits in neuronal development.
The role of α, β, and γ subunits of Na,K-ATPase with cancer.
Disorders related to mutations in α-subunits of the Na,K-ATPase.
Disorders related to β-subunits.
Disorders related to FXYD proteins.

Dr. Liora Shoshani
Guest Editor

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Keywords

Na⁺,K⁺-ATPase
α-subunit
β-subunit
γ subunits
FXYD

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Research

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13 pages, 2634 KiB

Open AccessArticle

Molecular Structure of the Na⁺,K⁺-ATPase α4β1 Isoform in Its Ouabain-Bound Conformation

by Kazuhiro Abe, Jeff McDermott, Hridya Valia Madapally, Parthiban Marimuthu, Chai C. Gopalasingam, Christoph Gerle, Hideki Shigematsu, Himanshu Khandelia and Gustavo Blanco

Int. J. Mol. Sci. 2024, 25(22), 12397; https://doi.org/10.3390/ijms252212397 - 19 Nov 2024

Viewed by 1491

Abstract

Na⁺,K⁺-ATPase is the active ion transport system that maintains the electrochemical gradients for Na⁺ and K⁺ across the plasma membrane of most animal cells. Na⁺,K⁺-ATPase is constituted by the association of two major subunits, a catalytic α and a glycosylated β subunit, both of which exist as different isoforms (in mammals known as α1, α2, α3, α4, β1, β2 and β3). Na⁺,K⁺-ATPase α and β isoforms assemble in different combinations to produce various isozymes with tissue specific expression and distinct biochemical properties. Na⁺,K⁺-ATPase α4β1 is only found in male germ cells of the testis and is mainly expressed in the sperm flagellum, where it plays a critical role in sperm motility and male fertility. Here, we report the molecular structure of Na⁺,K⁺-ATPase α4β1 at 2.37 Å resolution in the ouabain-bound state and in the presence of beryllium fluoride. Overall, Na⁺,K⁺-ATPase α4 structure exhibits the basic major domains of a P-Type ATPase, resembling Na⁺,K⁺-ATPase α1, but has differences specific to its distinct sequence. Dissimilarities include the site where the inhibitor ouabain binds. Molecular simulations indicate that glycosphingolipids can bind to a putative glycosphingolipid binding site, which could potentially modulate Na⁺,K⁺-ATPase α4 activity. This is the first experimental evidence for the structure of Na⁺,K⁺-ATPase α4β1. These data provide a template that will aid in better understanding the function Na⁺,K⁺-ATPase α4β1 and will be important for the design and development of compounds that can modulate Na⁺,K⁺-ATPase α4 activity for the purpose of improving male fertility or to achieve male contraception. Full article

(This article belongs to the Special Issue The Na, K-ATPase in Health and Disease)

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13 pages, 1624 KiB

Open AccessArticle

Na,K-ATPase Expression Can Be Limited Post-Transcriptionally: A Test of the Role of the Beta Subunit, and a Review of Evidence

by Elena Arystarkhova and Kathleen J. Sweadner

Int. J. Mol. Sci. 2024, 25(13), 7414; https://doi.org/10.3390/ijms25137414 - 6 Jul 2024

Viewed by 1465

Abstract

The Na,K-ATPase is an α–β heterodimer. It is well known that the Na,K-ATPase β subunit is required for the biosynthesis and trafficking of the α subunit to the plasma membrane. During investigation of properties of human ATP1A3 mutations in 293 cells, we observed a reciprocal loss of endogenous ATP1A1 when expressing ATP1A3. Scattered reports going back as far as 1991 have shown that experimental expression of one subunit can result in reduction in another, suggesting that the total amount is strictly limited. It seems logical that either α or β subunit should be rate-limiting for assembly and functional expression. Here, we present evidence that neither α nor β may be limiting and that there is another level of control that limits the amount of Na,K-ATPase to physiological levels. We propose that α subunits compete for something specific, like a private chaperone, required to finalize their biosynthesis or to prevent their degradation in the endoplasmic reticulum. Full article

(This article belongs to the Special Issue The Na, K-ATPase in Health and Disease)

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35 pages, 3685 KiB

Open AccessReview

Molecular Basis of Na, K–ATPase Regulation of Diseases: Hormone and FXYD2 Interactions

by Bárbara Martins Cordeiro, Carlos Frederico Leite Fontes and José Roberto Meyer-Fernandes

Int. J. Mol. Sci. 2024, 25(24), 13398; https://doi.org/10.3390/ijms252413398 - 13 Dec 2024

Viewed by 1501

Abstract

The Na, K–ATPase generates an asymmetric ion gradient that supports multiple cellular functions, including the control of cellular volume, neuronal excitability, secondary ionic transport, and the movement of molecules like amino acids and glucose. The intracellular and extracellular levels of Na⁺ and K⁺ ions are the classical local regulators of the enzyme’s activity. Additionally, the regulation of Na, K–ATPase is a complex process that occurs at multiple levels, encompassing its total cellular content, subcellular distribution, and intrinsic activity. In this context, the enzyme serves as a regulatory target for hormones, either through direct actions or via signaling cascades triggered by hormone receptors. Notably, FXYDs small transmembrane proteins regulators of Na, K–ATPase serve as intermediaries linking hormonal signaling to enzymatic regulation at various levels. Specifically, members of the FXYD family, particularly FXYD1 and FXYD2, are that undergo phosphorylation by kinases activated through hormone receptor signaling, which subsequently influences their modulation of Na, K–ATPase activity. This review describes the effects of FXYD2, cardiotonic steroid signaling, and hormones such as angiotensin II, dopamine, insulin, and catecholamines on the regulation of Na, K–ATPase. Furthermore, this review highlights the implications of Na, K–ATPase in diseases such as hypertension, renal hypomagnesemia, and cancer. Full article

(This article belongs to the Special Issue The Na, K-ATPase in Health and Disease)

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20 pages, 909 KiB

Open AccessReview

Role of Na⁺-K⁺ ATPase Alterations in the Development of Heart Failure

by Naranjan S. Dhalla, Vijayan Elimban and Adriana Duris Adameova

Int. J. Mol. Sci. 2024, 25(19), 10807; https://doi.org/10.3390/ijms251910807 - 8 Oct 2024

Cited by 1 | Viewed by 2461

Abstract

Na⁺-K⁺ ATPase is an integral component of cardiac sarcolemma and consists of three major subunits, namely the α-subunit with three isoforms (α₁, α₂, and α₃), β-subunit with two isoforms (β₁ and β₂) and γ-subunit (phospholemman). This enzyme has been demonstrated to transport three Na and two K ions to generate a trans-membrane gradient, maintain cation homeostasis in cardiomyocytes and participate in regulating contractile force development. Na⁺-K⁺ ATPase serves as a receptor for both exogenous and endogenous cardiotonic glycosides and steroids, and a signal transducer for modifying myocardial metabolism as well as cellular survival and death. In addition, Na⁺-K⁺ ATPase is regulated by different hormones through the phosphorylation/dephosphorylation of phospholemman, which is tightly bound to this enzyme. The activity of Na⁺-K⁺ ATPase has been reported to be increased, unaltered and depressed in failing hearts depending upon the type and stage of heart failure as well as the association/disassociation of phospholemman and binding with endogenous cardiotonic steroids, namely endogenous ouabain and marinobufagenin. Increased Na⁺-K⁺ ATPase activity in association with a depressed level of intracellular Na⁺ in failing hearts is considered to decrease intracellular Ca²⁺ and serve as an adaptive mechanism for maintaining cardiac function. The slight to moderate depression of Na⁺-K⁺ ATPase by cardiac glycosides in association with an increased level of Na⁺ in cardiomyocytes is known to produce beneficial effects in failing hearts. On the other hand, markedly reduced Na⁺-K⁺ ATPase activity associated with an increased level of intracellular Na⁺ in failing hearts has been demonstrated to result in an intracellular Ca²⁺ overload, the occurrence of cardiac arrhythmias and depression in cardiac function during the development of heart failure. Furthermore, the status of Na⁺-K⁺ ATPase activity in heart failure is determined by changes in isoform subunits of the enzyme, the development of oxidative stress, intracellular Ca²⁺-overload, protease activation, the activity of inflammatory cytokines and sarcolemmal lipid composition. Evidence has been presented to show that marked alterations in myocardial cations cannot be explained exclusively on the basis of sarcolemma alterations, as other Ca²⁺ channels, cation transporters and exchangers may be involved in this event. A marked reduction in Na⁺-K⁺ ATPase activity due to a shift in its isoform subunits in association with intracellular Ca²⁺-overload, cardiac energy depletion, increased membrane permeability, Ca²⁺-handling abnormalities and damage to myocardial ultrastructure appear to be involved in the progression of heart failure. Full article

(This article belongs to the Special Issue The Na, K-ATPase in Health and Disease)

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