Na+/H+ antiport activity

Blumwald, E. Poole, R.J. (1987). Salt tolerance in suspension cultures of sugar beet. Induction of Na /H" antiport activity at the tonoplasts by growth and salt. Plant Physiology, 83, 884-7. 

Sun, IX., Toole-Simms, W, Crane, F.L., Morre, D.J., Low, H., Chou, J.Y. (1988). Reduction of diferric transferrin by SV40 transformed pineal cells stimulates the Na+/H+ antiport activity. Biochim. Biophys. Acta 938, 17-23. 

In order to explain the Na stimulation of ATP synthesis driven by a diffusion potential the presence of a Na /H antiporter was proposed [175]. In this artificial system the acidification of the cytoplasm, which occurs in response to electrogenic potassium efflux, could be prevented by the antiporter. Subsequently, Na /H antiporter activity has been demonstrated in both Methanobacterium thermoautotrophicum [176] and in Methanosarcina harden [108]. An important result of these studies was that the Na /H antiporter could be inhibited by amiloride and harmaline, which have been described as inhibitors of eucaryotic Na" /H" antiporters [177]. Using these inhibitors it has been shown that an active antiporter is essential for methanogenesis from H2/CO2 [176,178]. The antiporter also accepts Li instead of Na, since Li stimulates CH4 formation from H2/CO2 in the absence of Na [176]. In subsequent studies the use of amiloride and the more potent derivative ethyl-isopropylamiloride permitted the discrimination of primary and secondary Na potentials generated in partial reactions of the CO2 reduction pathway. 

Northrup, T. E., Garella, S Perticucci, E-, and Cohen,]. J. (1983). Acidemia alone does not stimulate rat renal Na -H antiporter activity. Am. J. Piiysiol. 259, E 7-F243,... 

In the kidneys, PTH (1) induces 25-hydroxyvitamin D-la-hydroxylase, increasing the production of l,25(OH)2D, which stimulates intestinal absorption of both calcium and phosphate, (2) increases calcium reabsorption in the distal convoluted tubule of the nephron, (3) decreases reabsorption of phosphate by the proximal tubule, and (4) inhibits Na -H antiporter activity, which favors a mild hyperchloremic metabolic acidosis in hyperparathyroid states. 

Na+,H+ antiporters (NHE) occur in synaptosomes, glia and neuroblastoma cells [60] (Fig. 5-8B). They are relatively inactive at neutral pH but with a decrease in intracellular pH they produce an efflux of protons at the expense of the Na+ gradient. The NHE transport stoichiometry is 1 1. Activation by an internal pH decrement apparently results from protonation of a cytoplasmic site, which allosterically increases the affinity of the proton ionophoric site. In some cells, the NHE is under additional control by receptor mechanisms. Several growth factors and hormones produce transient cytoplasmic alkalinization, probably by mediating a protein kinase... 

MAPKAP MAP-kinase-activated protein kinase NHE Na+/H+ antiporter... 

The role of the Na+/H+ antiporter in human neutrophil NADPH-oxidase activation. J. Leuk. Biol. 43,183-6. 

Nofer JR, Tepel M, Kehrel B, et al. Low-density lipoproteins inhibit the Na H antiport in human platelets. A novel mechanism enhancing platelet activity in hypercholesterolemia. Circulation 1997 95 1370-1377. 

Frelin, C., Vigne, P., Breittmayer, J.P. (1990a). Palytoxin acidifies chick cardiac cells and activates the Na+/H+ antiporter. FEBS Lett. 264,63-66. 

Schwartz, M.A., Lechene, C., Ingher, D.E. (1991). Insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin Ctjp, independent of cell shape. Proc. Nad. Acad. Sci. USA 88, 7849-7853. 

Zhao, Z. Willis, J.S. (1993). Cold activation of Na influx through the Na+/H+ antiport of guinea pig red cells. J. Memb. Biol. 131,43-54. 

Parallel activation of Na+/H+ antiport and CI7HCO3 antiport Erythrocytes from dog, rabbit, and Amphiuma lymphocytes osteoclasts endothelial cells parotis pancreas, liver, gallbladder, proximale tubule, medullary thick ascending limb, and collecting duct MDCK cells Activation of Na+-K+-2CI cotransport... 

Like D2 receptors, when D3 receptors are transfected in heterologous systems, they are able to stimulate Na+/H+ exchange in the cells producing an acidification of the culture medium. This effect is due to the activation of the amiloride-sensitive Na+/H+ antiporter and is dependent on a Gi/Go protein activation and partly on the inhibition of cAMP production (Chio et al., 1994a Vanhauwe et al., 1999). However, the D3 receptor stimulation appeared to be less efficiently than that of D2 receptor on this response (Chio et al., 1994a Vanhauwe et al., 1999). 

Many compounds that perturb the cellular cytoskeleton affect phagocytosis and macropinocytosis. Binding to actin filaments by the natural product cytochalasin D blocks both of these uptake mechanisms. Disruption of microtubules by the antimitotic agents colchicine and nocodazole inhibits macropinocytosis and affects some mechanisms of phagocytosis. The diuretic drug amiloride, which is an inhibitor of Na+/H+ antiporters, selectively blocks macropinocytosis. By activating protein kinase C, phorbol esters represent a class of small molecules that promote macropinocytosis. 

The A/iNa formed may be converted via a Na /H antiporter into a AftfT which then drives the synthesis of ATP via a DCCD-sensitive H -translocating ATP synthase. This ATP formation explains net ATP synthesis coupled to acetate formation from H2/CO2 [192,195,199], Alternatively, A/lNa" could drive ATP synthesis directly via Na "-translocating ATP synthase. A Na -stimulated ATP-synthase activity has recently been reported for Acetobacterium woodii [200]. 

Methanol disproportionation includes two sites of A/xNa" generation (1) Methanol reduction generates a secondary AftNa from a primary A/IH" by the activity of the Na /H antiporter. This was concluded from the finding that CH4 formation from H2/CH3OH in Methanosarcina barkeri was coupled with Na extrusion, which was sensitive to Na /H antiporter inhibitors and protonophores [108]. (2) The oxidation of methylene-H4MPT to CO2 and 4[H] is coupled with the generation of a primary A/INa as indicated from the fact that Na translocation associated with formaldehyde conversion to CO2 and 2H2 was not sensitive towards Na /H antiporter inhibitors and protonophores [105]. 

Coupling of 0(2-ARs to G leads to inhibition of adenylyl cyclase, which results in decreased c AMP generation. Coupling to several other signaling pathways has also been reported for the o -ARs, including activation of K+ channels (230) inhibition of calcium channels activation of the Na+/H+ antiporter (231) and mobilization of intracellular Ca2+ (232). 

FIGURE 34.2 ABC transporters (green) that transport the substrate (S) in one defined direction are called primary transporters because no other additional biochemical step than the ATP hydrolysis or GSH co-transport is needed for (S) transport. SLC transporters (3, pink) need the activation by one or two ion transporters before S transport occurs. In this model, 1, is the Na+, K+-ATPase and 2, the Na, H antiporter providing the H driving force for S transport... 

Protein kinase C activation has been implicated in augmenting the transmembrane flux of calcium ions, the activities of the Na K -ATPase, as well as the activity of the Na /H -antiporter. Substantial evidence suggests that protein kinase C augments the uptake of calcium released during cellular stimulation, thereby limiting the temporal duration of its activation (e.g., phorbol esters activate the sarcoplasmic reticulum Ca -ATPase). 

Certain glycolytic enzymes appear to be target proteins for protein-tyrosine kinases. They may be responsible for the increased rate of glycolysis in transformed cells. The protein component of ion pumps may also be involved activation of Na+/H+ antiport systems causing mild alkalinization of the cells may play a role in stimulating mitosis. 

Na extrusion from plant cells is powered by the operation of the plasma membrane H -ATPase generating an electrochemical gradient that allows plasma membrane Na /H antiporters to couple the passive movement of inside the cells, along its electrochemical potential, to the active extrusion of Na [21]. Recently, AtSOSl from Arahidopsis thaliana has been shown to encode a plasma membrane Na /H antiport with significant sequence similarity to plasma membrane Na /H antiporters from bacteria and fungi [32]. The overexpression of SOSl improved the salt tolerance of Aro-hidopsis, demonstrating that improved salt tolerance can be attained by limiting Na accumulation in plant cells [33] (Table 10.1). 

Two cotransporters that are activated at low pH help maintain the cytosolic pH In animal cells very close to 7.4 despite metabolic production of carbonic and lactic acids. One, a Na /H antiporter, exports excess protons. The other, a Na HCOs /CP cotransporter, imports HCOs , which dissociates in the cytosol to yield pH-raising OH ions. 

Probes for the Na" channel and the Na /H antiporter amiloride analogs Na /K -ATPase ouabain probes Probes for channels and carriers glibenclamide conjugates for the ATP-dependent channel, apamin probes for small-conductance Ga -activated channels. 

Fig. 4.22. Hypoxia-mediated metabolic adaptation for energy preservation. Activation of genes for glucose transporter-1 (GLUT-1 = 1) and glycolytic enzymes yields an increased glycolytic rate. H -ions produced are preferentially exported via a Na /H -antiporter (NHE-1 = 3) and a lactate /H -symporter (monocarboxylate transporter MCT-1 = 2) leading to a drop in extracellular pH (pH.). Low extracellular pH activates the membrane-bound ectoenzyme carbonic anhydrase IX (CA IX = 4). Key mechanism regulating intracellular pH in tumor cells when protons are produced is also shown (Na -depen-dent HCOs" /CL -exchanger = 5). HIF-Ia = hypoxia-inducible factor la, PHDs = prolyl hydroxylases, FIH = asparagyl hydroxylase, lac" = lactic acid...

Plasma membranes of all cells investigated so far contain an electron transport system transferring electrons from NADH to an extracellular electron acceptor (for review, see Navas et al., 1994 and Chapter 4 of this volume). Electron transport across the plasma membrane is accompanied by release of protons from the cell, presumably due to an activation of the Na+/H+ antiport (Sun et a/., 1988). Since proton release and the concomitant increase in cytoplasmic pH have been connected to growth stimulation (Moolenar et al., 1983), it was proposed that the transplasma membrane redox system via proton release might also be involved in the regulation of proliferation. 

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