Na+/K+-transporting adenosine

Active Transport. Maintenance of the appropriate concentrations of K" and Na" in the intra- and extracellular fluids involves active transport, ie, a process requiring energy (53). Sodium ion in the extracellular fluid (0.136—0.145 AfNa" ) diffuses passively and continuously into the intracellular fluid (<0.01 M Na" ) and must be removed. This sodium ion is pumped from the intracellular to the extracellular fluid, while K" is pumped from the extracellular (ca 0.004 M K" ) to the intracellular fluid (ca 0.14 M K" ) (53—55). The energy for these processes is provided by hydrolysis of adenosine triphosphate (ATP) and requires the enzyme Na" -K" ATPase, a membrane-bound enzyme which is widely distributed in the body. In some cells, eg, brain and kidney, 60—70 wt % of the ATP is used to maintain the required Na" -K" distribution. 

Certain enzymes shown to be present in myelin could be involved in ion transport. Carbonic anhydrase has generally been considered a soluble enzyme and a glial marker but myelin accounts for a large part of the membrane-bound form in brain. This enzyme may play a role in removal of carbonic acid from metabolically active axons. The enzymes 5 -nucleotidase and Na+, K+-ATPase have long been considered specific markers for plasma membranes and are found in myelin at low levels. The 5 -nucleotidase activity may be related to a transport mechanism for adenosine, and Na+, K+-ATPase could well be involved in transport of monovalent cations. The presence of these enzymes suggests that myelin may have an active role in ion transport in and out of the axon. In connection with this hypothesis, it is of interest that the PLP gene family may have evolved from a pore-forming polypeptide [9],... 

The Na, K -ATPase is known to actively pump Na out and into a cell against their concentration gradients. The active transport of these ions is tightly coupled to hydrolysis of adenosine 5 -triphosphate (5 -ATP). For every molecule of 5 -ATP... 

Adenylate cyclase is considered as a second messenger that catalyzes the formation of cAMP (cyclic adenosine monophosphate) from ATP this results in alterations in intracellular cAMP levels that change the activity of certain enzymes—that is, enzymes that ultimately mediate many of the changes caused by the neurotransmitter. For example, there are protein kinases in the brain whose activity is dependent upon these cyclic nucleotides the presence or absence of cAMP alters the rate at which these kinases phosphorylate other proteins (using ATP as substrate). The phosphorylated products of these protein kinases are enzymes whose activity to effect certain reactions is thereby altered. One example of a reaction that is altered is the transport of cations (e.g., Na+, K+) by the enzyme adenosine triphosphatase (ATPase). 

ATP plays a central role in cellular maintenance both as a chemical for biosynthesis of macromolecules and as the major soirrce of energy for all cellular metabolism. ATP is utilized in numerous biochemical reactions including the eitric acid cycle, fatty acid oxidation, gluconeogenesis, glycolysis, and pyruvate dehydrogenase. ATP also drives ion transporters sueh as Ca -ATPase in the endoplasmic reticulum and plasma membranes, H+-ATPase in the lysosomal membrane, and Na+/K+-ATPase in the plasma membrane. Chemieal energy (30.5 kJ/mol) is released by the hydrolysis of ATP to adenosine diphosphate (ADP). 

Inhibition of carbonic anhydrase also decreases sodium entry into the posterior chamber. Sodium, transported by Na+-K+-adenosine triphosphatase, probably acts as the counter-ion for newly formed bicarbonate. These two ions are linked such that inhibition of either carbonic anhydrase or Na+-K+-adenosine triphosphatase reduces sodium movement into the posterior chamber. 

Figure 10-14 Ion and fluid movement in the nonpigmented ciliary epithelium. Na+ enters the nonpigmented ciliary epithelium from the stromal side either by diffusion or by NaVH+ exchange. Na+, the main cation involved in aqueous formation, is transported extraceUularly into the lateral intercellular channel by a Na+-K+-adenosine triphosphatase-dependent transport system. HC03 forms from the hydration of CO2, a reaction catalyzed by carbonic anhydrase. HC03", the major anion involved in aqueous formation, balances a portion of the Na+ being transported into the lateral intercellular channel. Cl" enters the intercellular space by a mechanism that is not understood. This movement of ions into the lateral intercellular space creates a hypertonic fluid, and water enters by osmosis. Because of the restriction on the stromal side of the channel, the newly formed fluid moves toward the posterior chamber. A rapid diffusional exchange of CO2 allows for its movement into the posterior chamber. (Adapted from Cole DF. Secretion of aqueous humor. Exp Eye Res 1977 25(suppl) l6l-176.)...

The effect on lOP of the cardiac glycosides, primarily digitaUs derivatives and ouabain, has been of interest for many years. The physiologic effects of these agents are produced by their ability to inhibit Na+K+ adenosine triphosphatase, and a ouabain-sensitive Na+K+ adenosine triphosphatase has been demonstrated in the ciliary epitheUum. In the ciliary nonpigmented epithelium, as in other types of secretory epitheUum, Na+K+ adenosine triphosphatase is thought to be responsible for the active transport of sodium, a process necessary for aqueous secretion to occur. 

Foscarnet competitively inhibits Na -Pj cotransport in animal and human kidney proximal tubule brush border membrane vesicles, reversibly inhibiting sodium-dependent phosphate transport [48, 49]. Renal cortical Na-K-ATPase and alkaline phosphatase activity are not inhibited by foscarnet, nor is proline, glucose, succinate, or Na" transport [48,49]. Foscarnet induces isolated phosphaturia without hypophosphatemia in thyroparathyroidectomized rats maintained on a low phosphorus diet, without affecting glomerular filtration rate, urinary adenosine 3 5 -cyclic monophosphate (cAMP) activity, or urinary calcium, sodium or potassium excretion [48,50]. Sodium-Pj cotransport in brush border membrane vesicles from human renal cortex was reported to be even more sensitive to inhibition by foscarnet than in rat renal brush border membrane vesicles [49]. 

Cyclodienes appear to act more in the central nervous system than in the peripheral nervous system. One major mode of action is the inhibition of y-aminobutyric acid-regulated Cl ion flux in neurons. Cyclodienes also exert effects on membrane-bound adenosine triphosphatases (ATPases), altering Na, K" ", and Ca " " ion transport. The result is a partial depolarization of neurons rather than repolarization... 

The nervous system is the main site of toxicity for DDT. Effects are observed on both the central nervous system (CNS) and peripherally. There is significant alteration of neuronal membrane enzymatic and electrophysiological properties. In particular, sodium channels are altered such that once activated they close slowly, prolonging the depolarization of the nerve by interfering with the active transport of Na ions out of the axon. Potassium channels are also affected. DDT specifically affects Na", K -adenosine triphosphatases (ATPases) and Ca " -AT-Pases, which inhibit repolarization of neurons. The membrane remains partially depolarized and is extremely sensitive to complete depolarization by very small stimuli. DDT also inhibits calmodulin that is necessary for Ca transport essential for the subsequent release of neurotransmitters. 

Thyroid hormones stimulate protein synthesis in most cells of the body. They also stimulate oxygen consumption by increasing the levels of the Na% K+-ATPase ion transporter. The generation of plasma membrane Na+ and K+gradients by the Na+, K+-ATPase is a major consnmer of cellular adenosine triphosphate (ATP), leading to stimulation of ATP synthesis in the mitochondria... 

---