Sodium-potassium ATPase channels

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. 

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). 

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." ... 

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. 

The ventricular action potential is depicted in Fig. 6-2.2 Myocyte resting membrane potential is usually -70 to -90 mV, due to the action of the sodium-potassium adenosine triphosphatase (ATPase) pump, which maintains relatively high extracellular sodium concentrations and relatively low extracellular potassium concentrations. During each action potential cycle, the potential of the membrane increases to a threshold potential, usually -60 to -80 mV. When the membrane potential reaches this threshold, the fast sodium channels open, allowing sodium ions to rapidly enter the cell. This rapid influx of positive ions... 

The striking compartmentalization of potassium in intracellular fluid, and of sodium in extracellular fluid, is a condition which is established and maintained by active transport across all plasma membranes. In the absence of active transport pumps, cotransporters and conductance channels, a directional, selective, rapid and regulated movement of potassium (or sodium) through the cell membranes would be impossible. The major molecular pathways of potassium permeation through plasma membranes are Na, K- ATPase, H-K-ATPase, Na-2C1-K-transporter, and potassium conductance channels (Peterson 1997). 

The membrane-bound Na, K-ATPase pump transports potassium ions into the cell, whilst simultaneously extruding sodium ions, and is driven by the simultaneous breakdown of ATP. Both ions are transported against their electrochemical concentration gradients. The energy in ATP is transformed into ion gradients for potassium and sodium, which subsequently provides the energy for the operation of secondary active potassium- and sodium-dependent cotransporters, and potassium-and sodium-selective conductance channels (Peterson 1997). 

Figure 15-6. Mechanisms of sodium, potassium, and hydrogen ion movement and water reabsorption in the collecting tubule cells. Synthesis of Na+/K+ ATPase and sodium and potassium channels is under the control of aldosterone, which combines with an intracellular receptor, R, before entering the nucleus. ADH acts on its receptor, V, to facilitate the insertion of water channels from storage vesicles into the luminal membrane. (Reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

Additional cellular events linked to the activity of blood pressure regulating substances involve membrane sodium transport mechanisms Na+/K.+ ATPase Na+fLi countertransport Na+ -H exchange Na+-Ca2+ exchange Na+-K+ 2C1 transport passive Na+ transport potassium channels cell volume and intracellular pH changes and calcium channels. 

Membrane-bound enzymes, particularly the ATPases involved in the ionic pumps for calcium, sodium and potassium, have been found to function abnormally in the brains of epileptic patients and animals. A reduction in Na+K+-ATPase activity has been reported in human focal epileptogenic tissue, but it is uncertain whether such changes are due to the disease itself or a reflection of drug treatment. Similar changes have, however, been reported in experimental animals following the localized application of alumina cream and in DBA/2 mice that exhibit sound-induced seizures a reduction in calcium-dependent ATPase has also been found in the brain of DBA/2 mice. Such findings are consistent with the hypothesis that a defect in ion channels may occur in epilepsy. 

Sodium and potassium cations are often encountered in the same biological environment and the transmembrane movements of both are required as part of an enzymatic pathway as in Na+, K+-ATPase. Under these circumstances it is essential that cation-specific channels are formed. What features of the channels contribute to the selectivity Earlier the preferred geometries of Na+and K+, sixfold octahedral and eightfold cubic respectively, were proposed as the main discriminatory factors. A computational analysis by Dudev and Lim [35] has considered the effect of coordinated water, number of available coordination sites in the channel walls, and the dipoles of the coordinating groups. The researchers investigated cation complexes with valinomycin and the protein KcsA, both K+-selective, and compared these with a non-selective NaK channel. 

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