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The Na+-K+-ATPase (Sodium Pump)


The Na+-K+-ATPase is a highly-conserved integral membrane protein that is expressed in virtually all cells of higher organisms. As one measure of their importance, it has been estimated that roughly 25% of all cytoplasmic ATP is hydrolyzed by sodium pumps in resting humans. In nerve cells, approximately 70% of the ATP is consumed to fuel sodium pumps.

Physiologic and Pathologic Significance

The ionic transport conducted by sodium pumps creates both an electrical and chemical gradient across the plasma membrane. This is critical not only for that cell but, in many cases, for directional fluid and electrolyte movement across epithelial sheets. Some key examples include:

  • The cell's resting membrane potential is a manifestation of the electrical gradient, and the gradient is the basis for excitability in nerve and muscle cells.
  • Export of sodium from the cell provides the driving force for several facilitated transporters, which import glucose, amino acids and other nutrients into the cell.
  • Translocation of sodium from one side of an epithelium to the other side creates an osmostic gradient that drives absorption of water. Important instances of this phenomenon can be found in the absorption of water from the lumen of the small intestine and in the kidney.

Depending on cell type, there are between 800,000 and 30 million pumps on the surface of cells. They may be distributed fairly evenly, or clustered in certain membrane domains, as in the basolateral membranes of polarized epithelial cells in the kidney and intestine.

Abnormalities in the number or function of Na+-K+-ATPases are thought to be involved in several pathologic states, particular heart disease and hypertension. Well-studied examples of this linkage include:

  • Several types of heart failure are associated with significant reductions in myocardial concentration of Na+-K+-ATPase.
  • Excessive renal reabsorption of sodium due to oversecretion of aldosterone has been associated with hypertension in humans.

Structure and Function

The Na+-K+-ATPase is composed of two subunits. The alpha subunit (~113 kD) is the action hero of the pair - it binds ATP and both sodium and potassium ions, and contains the phosphorylation site. The smaller beta subunit (~35 kDa glycoprotein) is absolutely necessary for activity of the complex. It appears to be critical in facilitating the plasma membrane localization and activation of the alpha subunit.

Several isoforms of both alpha and beta subunits have been identified, but aside from kinetic characterizations and tissue distribution, little is known regarding their differential physiologic importance.

Uncertainties remain in describing the structure of this molecule, but based on primary amino acid sequence, it is thought to possess 8 or 10 transmembrane domains. Considerable information is available to define the amino acids involved in ATP and cation binding.

Cation transport occurs in a cycle of conformational changes apparently triggered by phosphorylation of the pump. As currently understood, the sequence of events can be summarized as follows:

  • The pump, with bound ATP, binds 3 intracellular Na+ ions.
  • ATP is hydrolyzed, leading to phosphorylation of a cytoplasmic loop of the pump and release of ADP.
  • A conformational change in the pump exposes the Na+ ions to the outside, where they are released.
  • The pump binds 2 extracellular K+ ions, leading somehow to dephosphorylation of the alpha subunit.
  • ATP binds and the pump reorients to release K+ ions inside the cell.
  • The pump is ready to go again.

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Regulation of Sodium Pump Expression and Activity

Expression of sodium pump activity is regulated at multiple levels and in both acute and chronic timeframes. A functional pump requires synthesis and assembly of both alpha and beta subunits. In many cells excessive beta subunits are produced, making synthesis of alpha the rate-limiting step in expression. It should come as no surprise that such controls are physiologically complex and involve the action of multiple hormones.

Rapid changes in pump activity appear to reflect modulations in kinetic properties, induced by a variety of intracellular signalling pathways. Phosphorylation of the alpha subunit enhances pump activity, presumably by increasing turnover rate or affinity for substrates. A number of hormones stimulate kinase or phosphatase activities within the cell that affect pump activity. Also, it appears that some cell types contain an intracellular pool of pumps that can be rapidly recruited to a functional state in the plasma membrane.

Chronic or sustained changes in pump activity within cells is usually due to increases in transcription rate or mRNA stability.

Major hormonal controls over pump activity can be summarized as follows:

  • Thyroid hormones appear to be a major player in maintaining steady-state concentrations of pumps in most tissues. This effect appears to result from stimulation of subunit gene transcription.
  • Aldosterone is a steroid hormone with major effects on sodium homeostasis. It stimulates both rapid and sustained increases in pump numbers within several tissues. The sustained effect is due to enhanced transcription of the genes for both subunits.
  • Catecholamines have varied effects, depending on the specific hormone and tissue. For example, dopamine inhibits Na+-K+-ATPase activity in kidney, while epinephrine stimulates pump activity in skeletal muscle. These effects seem to be mediated via phosphorylation or dephosphorylation of the pumps.
  • Insulin is a major regulator of potassium homeostasis and has multiple effects on sodium pump activity. Within minutes of elevated insulin secretion, pumps containing alpha-1 and 2 isoforms have increased affinity for sodium and increased turnover rate. Sustained elevations in insulin causes upregulation of alpha-2 synthesis. In skeletal muscle, insulin may also recruit pumps stored in the cytoplasm or activate latent pumps already present in the membrane.

Pharmacology

The alpha subunit of the Na+-K+-ATPase is the receptor for cardiac glycosides such digitalis and ouabain. Different isoforms of the alpha subunit have different affinities for such glycosides. Binding of these widely-used drugs to sodium pumps specifically inhibits their activity.

Cardiac glycosides are widely used to increase the strength of contraction of the heart. Inhibition of sodium pump activity in cardiac myocytes results in an increase in intracellular sodium concentration. This leads to an increase in intracellular calcium concentration by sodium-calcium exchange, which appears to be the proximal mechanism for enhancing cardiac contractility.

References and Reviews

  • Ewart HS, Klip A: Hormonal regulation of the Na(+)-K(+)-ATPase: mechanisms underlying rapid and sustained changes in pump activity. Am J Physiol 269:C295, 1995.
  • Geering K: Na, K-ATPase. Curr Opin Nephrology Hypertension 6:434, 1994.
  • Jorgensen PL, Hakansson KO, Karlish SJD: Structure and mechanism of Na,K-ATPase: Functional sites and their interactions. Annu Rev Physiol 65:817-849, 2003.
  • Lingrel JB, Kuntzweiler T: Na+, K+-ATPase. J Biol Chem 269:19659, 1994.

Last updated on April 29, 2006
Original author: Laura Austgen
Send comments via form or email to rbowen@colostate.edu