Na+and K+-ATPase

Flavonoids can affect the function of plasma membrane transport Na+- and K+-ATPase, mitochondrial ATPase, and Ca2+-ATPase. The Mg2+-ectoATPase of human leukocytes is inhibited by quercetin, which acts as a competitor of ATP binding to the enzyme. The sarcoplasmic reticulum Ca2+-ATPase of muscle is effectively inhibited by several flavonoids that were also active inhibitors of antigen-induced mast cell histamine release. 

Studies on the modes of action of dialkylpiperidines have shown that these compounds cause diverse biochemical lesions. These alkaloids which are powerful hemolysins (26) and dermal necrotoxins (27, 28), also release histamine from mast cells ( 9), thus functioning as effective algogens. In addition, these fire ant products inhibit Na+ and K+ ATPases 30) and at low concentrations uncouple oxidative phosphorylation leading to reduced mitochondrial respiration (31). 2,6-Disubstituted... 

Flier, J., Edwards, M. W., Daly, J. W., and Myers, C. W., 1980, Widespread occurrence in frogs and toads of skin compounds interacting with the oubain site of Na and K" "ATPase, Science, 208 503. 

It is widely known that the ATPases can be distinguished on the basis of the cations that activate them. Mg2+-, Mg2+ plus Ca2+ and Mg2+ plus Na+ and K+-ATPases are probably the best known. They are also distinguished by their localization in different subcellular organelles and by their functions, especially on account of their participation or failure to participate in a proton or Ca2+ or Na+-K+ pump. We know of no specific function assigned to the microsomal ATPases from nervous tissue. Recently Trams Lauter (1974) and Stefanovic et al. (1976) have shown that in cultured mouse neuroblastoma and glial cells the ATPases are present in the external surface of the cell. These ATPases, for which the normal relationship to their assumed substrates still has to be determined, are inactive in the presence of 1 mM EDTA and are reactivated by Ca2+, Mg2+, Mn2+, Co2+, Cd2+ and other divalent cations. 

Fox et al. (2008) reported that in rat retinal rod cells, apoptosis accompanied high Pb exposures in vivo while low exposures induced cell proliferation. There were also decreases in Na" and K -ATPase activity. Wu et al. (2008) probed epigenetic changes in the brains of aging monkeys by using the epigenetic endpoints DNA methyltransferase and mRNA expression of P-amyloid precursor protein, transcription factor Spl. Infancy exposures... 

The Na - and K -dependent ATPase comprises two subunits, an a-subunit of 1016 residues (120 kD) and a 35-kD /3-subunit. The sodium pump actively... 

Protective effect of Na and K against inactivation of Na/K ATPase by high concentrations of 2-mercaptoethanol at high temperatures. Biochim. Biophys. Acta 821, 115-120. 

In biological systems, therefore, the behavior of Li+ is predicted to be similar to that of Na+ and K+ in some cases, and to that of Mg2+ and Ca2+ in others [12]. Indeed, research has demonstrated numerous systems in which one or more of these cations is normally intrinsically involved, including ion transport pathways and enzyme activities, in which Li+ has mimicked the actions of these cations, sometimes producing inhibitory or stimulatory effects. For example, Li+ can replace Na+ in the ATP-dependent system which controls the transport of Na+ through the endoplasmic reticulum Li+ inhibits the activity of some Mg2+-dependent enzymes in vitro, such as pyruvate kinase and inositol monophosphate phosphatase Li+ affects the activity of some Ca2+-dependent enzymes— it increases the levels of activated Ca2+-ATPase in human erythrocyte membranes ex vivo and inhibits tryptophan hydroxylase. 

Figure 9.6 A model for the active transport of Na+ and K+ by the (Na+-K+)-ATPase. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

The outcome of this is to couple ATP hydrolysis with the vectorial transport of Na+ and K+ across the plasma membrane. The inhibition of the (Na+-K+)-ATPase by cardiac glycosides such as digitalis (an extract of foxglove leaves), which blocks the dephosphorylation of the E2-P form of the enzyme, is the basis for a number of steroid drags which are commonly prescribed for the treatment of congestive heart failure. 

The experiments were continued by Hoffman and Whittam, who concluded that a protein, an ATPase, in the membrane was necessary for active transport and was vectorially organized, with ATP and Na+ being required internally and K+ externally where ouabain was inhibitory. The ATPase was finally identified as the sodium pump by Skou (1957) it vectorially translocated Na+ and K+ across the membrane, and was phosphorylated transiently in the process. 

A valuable clue to the manner in which iron pump functions, came in 1957 when an enzyme of molar mass 110 kg/mol was discovered by Jens Skou which hydrolyses ATP only if Na and K+ ions are present in addition to Mgt+ required for all ATPases (enzymes catalysing the hydrolysis of ATP). The activity of this enzyme correlates quantitatively with the extent of ion transport. Another important clue was provided by the observation that this ATPase is phosphorylated at an aspartase site only in the presence of Na+ and Mg2+ ions. The phosphorylated product is hydrolysed if K+ ions are present. It has been also observed that the enzyme undergoes a conformational change when it is phosphorylated. 

Professor Eisenman, there is a large body of results indicating the existence of channel systems. One could mention the Ca2+ ATPase of sarcoplasmic reticulum, the FF transporting ATPase of the inner mitochondrial membrane, the purple protein system of halobacteria, the Na and K+ channels of the axonal membranes. Apart from the classical type of evidence provided, for example, by the noise fluctuation technique, we now even begin to see direct electron microscopic evidence for the existence of transport-related openings in biological membranes. On the other hand, solid evidence for the existence of mobile carriers in eucaryotic cell membranes is very scarce, if not outright absent. 

In virtually every animal cell type, the concentration of Na+ is lower in the cell than in the surrounding medium, and the concentration of K+ is higher (Fig. 11-36). This imbalance is maintained by a primary active transport system in the plasma membrane. The enzyme Na+K+ ATPase, discovered by Jens Slcou in 1957, couples breakdown of ATP to the simultaneous movement of both Na+ and K+ against their electrochemical gradients. For each molecule of ATP converted to ADP and I , the transporter moves two K+ ions inward and three Na+ ions outward across the plasma membrane. The Na+K+ ATPase is an integral protein with two subunits (Mr -50,000 and -110,000), both of which span the membrane. 

FIGURE 11-36 Na+K+ ATPase. In animal cells, this active transport system is primarily responsible for setting and maintaining the intracellular concentrations of Na+ and K+ and for generating the transmembrane electrical potential. It does this by moving three Na+ out of the cell for every two K+ it moves in. The electrical potential is central to electrical signaling in neurons, and the gradient of Na+ is used to drive the uphill cotransport of solutes in many cell types. 

In animal cells, Na+K+ ATPase maintains the differences in cytosolic and extracellular concentrations of Na+ and K+, and the resulting Na+ gradient is used as the energy source for a variety of secondary active transport processes. 

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