The Sodium—Potassium ATPase

Mammalian cells maintain a lower concentration of Na (around 12 mM) and a higher concentration of (around 140 mM) than in the surrounding extracellular medium (respectively 145 mM and 4 mM). The Na -K -ATPase which maintains high intracellular and low intracellular Na is localised in the plasma membrane, and belongs to the family of P-type ATPases. Other members of the family in eukaryotes are the sarcoplasmic 

FIGURE 9.8 Transmembrane organisation of sodium channel a-subunit. Right 3-D structure of the a-subunit at 0.2 nm resolution. From Yu et al., 2005. Reproduced with permission of Blackwell Publishing Ltd.) 

This results in the extrusion of three positive charges for every two which enter the cell, resulting in a transmembrane potential of 50—70 mV, and has enormous physiological significance. More than one-third of the ATP utilised by resting mammalian cells is used to maintain the intracellular Na —K gradient (in nerve cells this can rise to up to 70%), which controls cell volume, allows neurons and muscle cells to be electrically excitable, and also drives the active transport of sugars and of amino acids (see later). 

FIGURE 9.10 PDB structures and conservation of P-type ATPases. (a) Topology diagram of atypical P-type ATPase a-subunit with 10 TM helices, (b) Sequence conservation among human P-type ATPases. Highly conserved residues (magenta spheres) cluster in the P-domain. From Bublitz et al, 2010. Reproduced with permission from Elsevier.) 

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The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

Glitsch, H. G. Electrophysiology of the sodium-potassium -ATPase in cardiac cells. Physiol. Rev. 81 1791-1826,2001. 

Nerve stimulation results in a net influx of sodium ions, and normal conditions are restored by the outward transport of sodium ions against an electrochemical gradient. While several earlier workers had identified ATPases in the sheath of giant squid axons, it was Skou who first connected the sodium, potassium ATPase [EC 3.6.1.37] with the ion flux of neurons. This discovery culminated... 

Inorganic ions, such as sodium and potassium, move through the cell membrane by active transport. Unlike diffusion, energy is required for active transport as the chemical is moving from a lower concentration to a higher one. One example is the sodium-potassium ATPase pump, which transports sodium [Na ] ions out of the cell and potassium [K ] into the cell. 

This must obviously be the opposite of passive transport. Active transport does require energy, usually in the form of the consumption of ATP or GTP, because the molecules are moving against the concentration gradient from an area of lower concentration to an area of higher concentration. The most well known active transport system is the Sodium-Potassium-ATPase Pump (Na" "- K+ZATPase) which maintains an imbalance of sodium and potassium ions inside and outside the membrane, respectively. See Figure 3. 

Extrapolating from well-characterized enzymatic inhibition in test tubes, numerous mechanistic ideas concerning the in vivo effects of vanadium compounds have been advanced. The effects of vanadium compounds as transition-state analogs of certain enzymes with a phosphoprotein intermediate in their reaction scheme is proposed to account for the action of vanadium [11] in many biological systems. Unfortunately, it is often difficult to determine if the inhibition observed in the test tube occurs in vivo. For example, although vanadate is a potent inhibitor of plasma membrane ion pumps (such as the sodium potassium ATPase) in the test tube, it is difficult to determine if these pumps are actually inhibited in animals exposed to vanadium compounds. Currently, the role of vanadium compounds as protein phosphatase (PTP) inhibitors is believed to be related to the metabolic effects of this... 

The relationship of intracellular sodium to intracellular calcium is such that a very small increase in sodium in terms of percentage increase leads to a disproportionately large increase in calcium. Therefore, a direct effect on the sodium/potassium-ATPase to inhibit sodium pump activity is the primary mechanism of the positive inotropic effect of the cardiac glycosides, while secondary elevation of intracellular calcium provides the ionic punch to increase contractility. A diagram of the relationship between sodium/potassium-ATPase and calcium is shown in Figure 12.6. 

The state of the sodium channel varies in healthy ventricular cells and those damaged by ischemia. This variability in the state has implications for antiarrhymic therapy with sodium channel blocking agents. In sick or damaged ventricular cells (i.e., from ischemia or blockade of the sodium/potassium-ATPase [sodium/potassium pump]), the resting membrane is more positive than the healthy resting membrane potential (Figure 12.10). 

Many substances can be transported into the cell (and vice versa) against a concentration gradient. This is an active transport process, and it requires energy in the form of ATR It is to be distinguished from a passive transport process, which is simple diffusion across membranes. One of the better understood systems of this type is the sodium-potassium ATPase (or Na/K) pump, which maintains high potassium and low sodium levels in the cell. These are up to 160 meq/L for K+ and about 10 meq/L of Na+ inside the cell. Extracellular fluid contains about 145 meq/L of Na+ and 4 meq/L of K+. The simultaneous movement of one substance out of the cell and another into the cell is an antiport. A substantial percentage of the basal metabolic rate (see Chapter 21) is accounted for by the activity of the Na/K pump. ATPase (Na/K pump) is lo-... 

Figure 9.28 Operation of the sodium-potassium ATPase. The process involves phosphorylation of the enzyme and binding of Na+ on the cytosol side of the membrane and K+ on the plasma (outer) side.

Prolactin also stimulates the sodium/potassium ATPase of the mammary gland, leading to uptake of potassium ions and extrusion of sodium ions from the epithelial cells [78]. Via this and other effects the hormone probably plays an important part in regulating salt and water relationships in the mammary gland. Milk secretion involves a considerable loss of both water and salts from the mother, and control of these is of crucial importance. 

The predominant buffers in the urine are phosphate (HP042 ) and ammonia (NH3). Phosphate is freely filtered by the glomerulus and passes down the tubule where it combines with H+ to form Hd Oy. Hydrogen ions are secreted in exchange for sodium ions the energy for this exchange comes from the sodium-potassium ATPase that maintains the concentration gradient for sodium. 

Uncoupling of the respiratory chain due to stimulation of the sodium/potassium ATPase... 

The E2-P state of the sodium/potassium ATPase binds which of the following ... 

ATPase. An enzyme that hydrolyzes ATP to yield ADP and phosphate usually coupled to some process requiring energy such as the sodium potassium ATPase. 

Cain, C. C. Sipe, D. M. Murphy, R. F. Regulation of endocytic pH by the sodium-potassium ATPase in living cells. Proc. Natl. Acad. Sci. USA 1989, 86, 544-548. 

Pharmacology and Mechanism of Action. The exact mechanism of action of ethosuximide remains elusive. Proposed mechanisms include inhibition of NADPH-linked aldehyde reductase, inhibition of the sodium-potassium ATPase system, a decrease in noninactivating Na+ currents, blocking of Ca +-dependent K+ channels, and inhibition of T-type Ca + channel currents." ... 

Figure 8.9. Physiology and molecular biology of intestinal bile acid transport. Bile acids are actively absorbed in enterocytes through a sodium-dependent cotransporter, ASBT. The sodium gradient is maintained by the sodium-potassium ATPase, located at the basolateral membrane. In the ( osol, bile acids are shuttled through the cell by the aid of various proteins, most importantly the ileal hille acid binding protein, iBABP. An anion exchanger transports bile acids across the basolateral membrane into the portal circulation.

The sodium-potassium pump (also called the sodium-potassium ATPase) is an ion pump in the membranes of cells that pumps sodium out as it pumps potassium into the cell (Figure 10.25). The energy source for the pumping action is the hydrolysis of ATP. The sodium-potassium pump is important in maintaining the osmotic balance of the cell. It can be inhibited by the glycoside called ouabain. 

Lithium readily enters excitable cells via sodium channels. It is not. however, removed well by the sodium/potassium ATPase exchange mechanism. It therefore accumulates within the cell. Thus, the intracellular concentration of potassium is decreased as the influx of potassium is reduced, both through inhibition of active transport (by Na+/K+ ATPase) and the decrease in the electrical gradient for potassium. Extracellular potassium therefore increases. The reversal in potassium levels results in a decrease in neuronal excitability, producing a therapeutic calming effect. 

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