Other Topics

Sodium Pumps: The Sodium-Potassium ATPase

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:

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:

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:

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:

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


Send comments to Richard.Bowen@colostate.edu