Elsevier

Seminars in Nephrology

Volume 26, Issue 5, September 2006, Pages 386-392
Seminars in Nephrology

Na+, K+-ATPase: An Indispensable Ion Pumping-Signaling Mechanism Across Mammalian Cell Membranes

https://doi.org/10.1016/j.semnephrol.2006.07.002Get rights and content

Na+, K+-adenosine triphosphatase is a ubiquitous enzyme present in higher eukaryotes responsible for the maintenance of ionic gradients across the plasma membrane. It creates appropriate conditions for critical cellular processes such as secondary transport of solutes and water, for pH regulation, and also for creating an electrical potential that gives singular qualities to excitable cells. It also served as a platform for a higher level of cellular complexity because many important signaling networks appear to be downstream events of the pump’s function. Renal physiology and pathology are affected significantly by its presence, and it seems that both molecular and pharmacologic manipulations of its action can create different venues to deal with diverse disease states.

Section snippets

Evolutionary Considerations of the Na+, K+-ATPase

The curious connection between the sessile nature of plants and the absence of a cell volume-regulating system such as the Na+, K+-ATPase was observed by Krogh more than 50 years ago. Contrary to plants, animal cells have this exquisite volume-regulating system but reciprocally lack a rigid cell wall that would limit their motility.4 Plant cells regulate their volume in such a singular way that they can even create an intracellular osmotic force that attracts water by accumulating Na+ in

Ionic Transporter and Signal Transducer

Apart from allowing cells to deal with the sodium stress, Na+, K+-ATPase gave rise to an even higher level of sophistication by guiding hierarchic cellular functions such as motility, polarity, and signaling. It has been shown convincingly that Na+, K+-ATPase is a signal transducer.15 This quality appears to have arisen independently from the ion transport function during its evolution because the specific binding motifs that transfer signals are located outside the conserved regions common to

Na+, K+-ATPase Function: Impact in Health and Disease States

The mechanisms described previously suggest that Na+, K+-ATPase functions may be dissociated, one indirectly affecting cellular complexity through the transport of ions, which allows cells to cope with sodium stress and emerge as a consequence of the evolutionary pressure, and the other directly causing the cellular complexity by altering signaling pathways. It is worth emphasizing that some signaling functions not related to ion transport have been described clearly, although domain-dependent

Conclusions

The appearance of Na+, K+-ATPase is a significant event in evolution. Its intrinsic properties make the simultaneous occurrence of advanced cellular processes with their inherent fragilities possible. Also, it allowed the existence of new phenomena such as its signaling properties, which are of paramount importance for diverse cellular processes. Discovering that Na+, K+-ATPase activity could be affected in a short-term fashion in intact cells in response to physiologic agonists was critical

Acknowledgments

The constructive criticisms of Adrian I. Katz and Cara Gottardi are greatly appreciated.

References (82)

  • R. Efendiev et al.

    Intracellular Na+ regulates dopamine and angiotensin II receptors availability at the plasma membrane and their cellular responses in renal epithelia

    J Biol Chem

    (2003)
  • J. Liu et al.

    Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism

    Kidney Int

    (2004)
  • S.M. Periyasamy et al.

    Salt loading induces redistribution of the plasmalemmal Na/K-ATPase in proximal tubule cells

    Kidney Int

    (2005)
  • K. Mohammadi et al.

    Role of protein kinase C in the signal pathways that link Na+/K+-ATPase to ERK1/2

    J Biol Chem

    (2001)
  • P. Kometiani et al.

    Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytesThe roles of Ras and mitogen-activated protein kinases

    J Biol Chem

    (1998)
  • Z. Xie et al.

    Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes

    J Biol Chem

    (1999)
  • H. Amlal et al.

    Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading

    Kidney Int

    (2001)
  • M.P. Fink

    Cytopathic hypoxiaMitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis

    Crit Care Clin

    (2001)
  • M.P. Fink et al.

    Epithelial barrier dysfunction: A unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level

    Crit Care Clin

    (2005)
  • K. Sugi et al.

    Inhibition of Na+,K+-ATPase by interferon gamma down-regulates intestinal epithelial transport and barrier function

    Gastroenterology

    (2001)
  • M.R. Harrigan

    Cerebral salt wasting syndrome

    Crit Care Clin

    (2001)
  • B.F. Palmer

    Hyponatremia in patients with central nervous system disease: SIADH versus CSW

    Trends Endocrinol Metab

    (2003)
  • A.A. McDonough et al.

    Role of muscle in regulating extracellular [K+]

    Semin Nephrol

    (2005)
  • J.C. Skou

    Nobel lectureThe identification of the sodium pump

    Biosci Rep

    (1998)
  • I.M. Glynn

    A hundred years of sodium pumping

    Annu Rev Physiol

    (2002)
  • W.D. Stein

    The sodium pump in the evolution of animal cells

    Philos Trans R Soc Lond B Biol Sci

    (1995)
  • H.J. Bohnert et al.

    Adaptations to environmental stresses

    Plant Cell

    (1995)
  • J.H. Kaplan

    A moving new role for the sodium pump in epithelial cells and carcinomas

    Sci STKE pe31

    (2005)
  • W. Kuhlbrandt

    Biology, structure and mechanism of P-type ATPases

    Nat Rev Mol Cell Biol

    (2004)
  • B. Alberts

    Molecular Biology of the Cell (ed 4)

    (2002)
  • W.F. Boron

    Regulation of intracellular pH

    Adv Physiol Educ

    (2004)
  • Z. Xie et al.

    Na(+)/K(+)-ATPase as a signal transducer

    Eur J Biochem

    (2002)
  • Z. Xie et al.

    Na+-K+-ATPase-mediated signal transduction: From protein interaction to cellular function

    Mol Interv

    (2003)
  • S.C. Ward et al.

    Novel receptors for ouabain: Studies in adrenocortical cells and membranes

    Hypertension

    (2002)
  • R.G. Contreras et al.

    Relationship between Na(+),K(+)-ATPase and cell attachment

    J Cell Sci

    (1999)
  • M. Cereijido et al.

    Cell adhesion, polarity, and epithelia in the dawn of metazoans

    Physiol Rev

    (2004)
  • C.J. Gottardi et al.

    An ion-transporting ATPase encodes multiple apical localization signals

    J Cell Biol

    (2003)
  • T.R. Muth et al.

    Transport protein trafficking in polarized cells

    Annu Rev Cell Dev Biol

    (2003)
  • E. Rodriguez-Boulan et al.

    Polarity signals in epithelial cells

    J Cell Sci Suppl

    (1993)
  • C. Zurzolo et al.

    Glycosylphosphatidylinositol-anchored proteins are preferentially targeted to the basolateral surface in Fischer rat thyroid epithelial cells

    J Cell Biol

    (1993)
  • L. Shoshani et al.

    The polarized expression of Na+,K+-ATPase in epithelia depends on the association between beta-subunits located in neighboring cells

    Mol Biol Cell

    (2005)
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    Supported in part by Swedish Research Council grants 32X-10860 and 32P-1489.

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