The Na H exchanger

Primarily using isolated plasma membrane vesicles as an experimental preparation, the functional properties of Na /H exchangers have been elucidated. The important kinetic properties include (1) stoichiometry (one-for-one) (2) reversibility (3) substrate specificity (monovalent cations Na, H, Li, NH4, but not K, Rb, Cs, choline) (4) modes of operation (Na -for-H, Na -for-Na Li -for-Na, Na -for-NH4 ) (5) existence of an internal site for allosteric activation by (6) reversible inhibition by amiloride (Af-amidino-5-amino-6-chloropyr-azine carboxamide) and its 5-amino-substituted analogs and (7) competitive nature 

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Interestingly, Grinstein et al. [19] found that DCCD did not inhibit the Na /H" exchanger in thymic lymphocytes (sensitive-type) whereas Ganapathy et al. [18] found that the placental brush border Na /H exchanger, which is also a sensitive-type, was susceptible to DCCD, and amiloride protected from inhibition. Thus, there may be structural differences between sensitive-type exchangers from these two tissues. 

Subsequently, proteolytic fragments of the rabbit renal 25-kDa amiloride-binding protein were micro-sequenced and found to have high sequence homology with rat and human NAD(P)H quinone oxidoreductase. Indeed, enzymatic assays revealed that renal brush border membrane vesicles contain significant NADPH quinone oxidoreductase activity. Presumably NAD(P)H quinone oxidoreductase coincidentally binds amiloride analogs with the same rank order as the Na /H exchanger [39]. 

Whereas the above studies have attempted to identify the Na /H exchanger in renal brush border membranes (a resistant-type), at least one study has reported possible identification of a sensitive-type transport protein [49]. The Na /H exchanger in lymphocytes (a sensitive-type) can be activated by either 12-0-tetradeca-noylphorbol 13-acetate (TPA) or osmotic shrinkage. TPA or osmotic shrinkage... 

Next, Reilly et al. [65] localized the Na /H exchanger gene product in renal epithelial cells where the distributions of the kinetic isoforms was well-established. The strategy was based on the observation that the resistant- and sensitive-types are restricted to the apical and basolateral membranes, respectively, in confluent LLC-PK]/Clone 4 cells [8]. Thus, if proteins encoded by the cloned cDNAs localized to the apical membrane this would indicate that they represent the resistant-type. Localization to the basolateral membrane would prove they were the sensitive-type and presence on both membranes would suggest that the two functional isoforms had identical primary structures. Na exchanger proteins were localized by... 

While the lactate-H+ symporter and the K+/H+ exchanger are involved in acidification of the cell, the Na+/H+ exchanger present in the basal cells exports protons out of the cell in exchange for Na+ [139]. It was observed that removal of Na+ from the Ringer s solution decreased intracellular pH by 0.5 unit in basal cells, possibly due to inhibition of the Na+/H+ exchanger. As the basal cells are the precursors for the superficial cells of the corneal epithelium, it is quite likely that similar exchange processes are also present in the superficial layer, the principal barrier to ion and drug transport [99,103],... 

I.N. Rich, D. Worthington-White, O.A. Garden, and P. Musk, Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+ exchanger. Blood 95, 1427-1434 (2000). 

In transfected cells, H3 receptor mediated activation of Gj/0 proteins has also been reported to modulate arachi-donic acid release [29] and the Na+/H+ exchanger [44], and to inhibit Ca2+ influx and exocytosis of [3H] noradrenaline from transfected SH-SY5Y-H3 cells [45], The inhibition of Ca2+ influx may be particularly relevant in view of the known physiological function of the brain H3 receptor. 

Figure 9.8 The Na+/H+ exchanger of bacteria and mammals. The driving force is provided, respectively, by the H+-ATPase (a) and the Na+/K+-ATPase (b) (From Orlowski and Grinstein 2004. With kind permission of Springer Science and Business Media.)...

As described in the paragraphs above, conclusions on a direct effect of any of these ions should be drawn with caution, since a change in the concentration of any of these may activate a regulatory mechanism to compensate for the change, for example the Na+/H+ exchanger, the Na+/HCC>3 symport or the Na+/Ca2+-exchange mechanism. 

Triamterene is known as a potassium-sparing diuretic. It interferes with the Na -H exchange and can be used in combination with thiazides in order to help alleviate the electrolyte deficiency which can occur with diuretic treatment. 

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