Seminars in Nephrology
Volume 25, Issue 5 , Page 281, September 2005

Introduction

Article Outline

 

In 1997, Jens Skou1 received the Nobel Prize in Chemistry for his discovery of the Na,K-pump, a breakthrough first reported in the late 1950s. As mentioned in the first article in this issue, the award recognized the central role played by this plasma membrane–spanning transport protein in cellular ionic homeostasis. The pump extrudes Na+ from the cell and absorbs K+ at the expense of adenosine triphosphate hydrolysis, thereby generating the electrochemical gradient that exists across the cell membrane. These gradients, in turn, provide the basis for nutrient uptake, control of intracellular pH and Ca2+, membrane excitability, and volume regulation. Recent studies have linked the pump to nontransport functions as well, including cell motility and hypertrophy.2, 3 The pump also plays a role in pathology, including polycystic kidney disease and hypertension.4, 5, 6 As the target of the digitalis glycosides, the Na,K-pump is a major locus for therapeutic intervention in congestive heart failure.7 One might think that given the many years since its discovery there would be little left to say about this transporter, but it remains the focus of intense research, with large and surprising gaps in our knowledge. Indeed, it now appears that the Na,K-pump may play roles in cellular physiology well beyond those envisioned by Skou and his colleagues. This issue explores those roles, placing them in a context that is relevant and accessible to the nephrologist or renal physiologist.

To achieve that purpose, I have enlisted the help of capable colleagues known for both their cutting-edge science and their ability to communicate well. Many will be familiar from their prominent exposure at scientific meetings. Others have caught my eye during the review of manuscripts or grant applications. Finally, most are friends whom I have known for many years. The first 3 articles explore the structure and composition of the Na,K-pump. A key breakthrough of recent years was the development of a high-resolution structure for the closely related Ca-pump, and Dwight Martin reviews how that model has influenced our understanding of structure-function relationships within the Na,K-pump. Gustavo Blanco then discusses a long-standing issue in the field, the unexpected heterogeneity seen in pump composition. Finally, Haim Garty and Steve Karlish take up the narrative with a description of a family of small regulatory proteins closely associated with the pump in some tissues, the FXYD proteins. The next 2 articles focus on regulation of the pump in the kidney. Manlio Vinciguerra, David Mordasini, Alain Vandewalle, and Eric Feraille outline the mechanisms underlying modulation of the pump in the collecting duct, and Carlos Pedemonte, Riad Efendiev, and Alejandro Bertorello describe the regulatory role played by membrane translocation of the pump in the proximal tubule. The remaining articles in this issue focus on the role of the Na,K-pump at the systemic level—a role that often goes beyond that of a simple transporter. Sigrid Rajasekaran, Sonali Barwe, and Ayyappan RajaseKaran discuss the influence of the pump on the establishment and maintenance of cell polarity. Alicia McDonough and Jang Youn then evaluate the role of the Na,K-pump of sarcolemma in controlling extracellular K+ concentrations. Although the inhibitory effects of the digitalis glycosides have been known for years, their importance as endogenous hormones only recently has been established, as described by Wilhelm Schoner and Georgios Scheiner-Bobis. Finally, this issue is closed by Gerald Kidder and Andrew Watson, who discuss the role played by the pump in development and differentiation.

Despite nearly a half century of investigation, it is hoped that the articles in this issue will show that the Na,K-pump continues to surprise us with its complexity and extensive involvement in homeostasis.

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References 

  1. Skou JC . The influence of some cations on an adenosine triphosphatase from peripheral nerves . Biochim Biophys Acta . 1957;23:394–401
  2. Kometiani P , Li J , Gnudi L , et al.   Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes (The roles of ras and mitogen-activated protein kinases) . J Biol Chem . 1998;273:15249–15256
  3. Rajasekaran SA , Palmer LG , Quan K , et al.   Na,K-ATPase β-subunit is required for epithelial polarization, suppression of invasion, and cell motility . Mol Biol Cell . 2001;12:279–295
  4. Herrera VLM , Ruiz-Opazo N . Alteration of α1 Na+,K+-ATPase 86Rb+ influx by a single amino acid substitution . Science . 1990;249:1023–1026
  5. Nishi A , Celsi G , Aperia A . High-salt diet upregulates activity and mRNA of renal Na+-K+-ATPase in Dahl salt-sensitive rats . Am J Physiol . 1993;264:F448–F452
  6. Wilson PD . Epithelial cell polarity and disease . Am J Physiol . 1997;272:F434–F442
  7. Schwinger RH , Bundgaard H , Muller-Ehmsen J , et al.   The Na,K-ATPase in the failing human heart . Cardiovasc Res . 2003;57:913–920

PII: S0270-9295(05)00045-8

doi:10.1016/j.semnephrol.2005.03.002

Seminars in Nephrology
Volume 25, Issue 5 , Page 281, September 2005

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