References


Hormonal Regulation and Mechanism of the Sodium Pump

of Mammalian Cell Membranes

All mammalian living cells show high intracellular K+ and low Na+ concentrations while the extracellular concentrations of Na+ are high and those of K+ are low. It is the sodium pump in mammalian cell membranes that achieves this physiological imbalance of univalent cations. It was Jens Christian Skou  , the Nobel laureate 1997, who first described in 1957 the existence of the sodium pump. This pump is essential in maintaining the membrane potential of living cells, to energize the transport of organic solutes by sodium symporters in epithelial cells and to indirectly regulate intracellular pH and Ca2+ concentration (Figure 1).

Figure 1: Function of Na+/K+-ATPase Figure 1

Na+/K+-ATPase (E.C.3.6.1.37), the equivalent of the sodium pump, uses the energy of the hydrolysis of 1 mole ATP to ADP and Pi to export 3 moles of Na+ out of the cell and to import 2 moles of K+ into the cell.. The essential kinetics of this pumping process are often described by the Albers-Post model (Figure 2). An important aspect of this model is the oscillation of the catalytic a subunit between "Na+ " and "K+ " conformations. This implies that a single subunit catalyzes the pumping process.

Figure 2
Figure 2: Mechanism of Na+/K+-ATPase

However, experiments performed in Giessen clearly show that an interaction of two a subunits and their ATP sites is needed to pump ions against their electrochemical gradient. Therefore, the sodium pump is working as a (ab)2-diprotomer, that contains Na+ und K+ conformations at the same time as well as cooperating high and low affinity ATP sites (Figure 3). On a molecular level it is still unknown, however, how the energy of ATP hydrolysis is converted into a vectorial transport process.
 
 
Figure 3
Figure 4
Figure 3: Distances in an (ab)2-diprotomer
Figure 4: Structure of Ouabain

Digitalis has been used successfully for over 200 years to treat patients having dropsy or heart failure. The cardiotonic steroid digitalis is a specific inhibitor of the sodium pump. Ouabain (Figure 4), another cardiotonic steroid, has recently be extracted and purified from bovine adrenals. It is secreted into the blood plasma upon activation of circulation. Others found in 50% of patients with essential hypertension increased concentrations of ouabain. Hence, ouabain is an essential factor in hypertension (Figure 5). Furthermore, and in analogy with other steroid hormones a specific binding globulin for cardiotonic steroids has been detected in blood plasma. It may protect cells against exceedingly high concentrations of the cardiotonic steroid hormone. The hormonal control of the release of ouabain from adrenals and the interaction of ouabain with other hormones participating in salt and water metabolism or of heart functions, is completely unknown so far, and warrants further investigation.

Figure 5

Figure 5: Regulation of the secretion of ouabain and its action on circulation.

At this point the Giessen Research Group is investigating:

The group is a member of the "Biomembranes" study group of GBM (Gesellschaft für Biochemie und Molekularbiologie).
 
 

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Version of  September 23, 2009 / ks
biochem@vetmed.uni-giessen.de