Na + -H + exchange system

Frelin, C., Vigne, P., Lazdunski, M. (1984). The role of the Na+/H+ exchange system in cardiac cells in relation to the control of the internal Na+ concentration. A molecular basis for the antagonistic effect of ouabain and amiloride on the heart. J. Biol. Chem. 259, 8880-8885. 

Sodium is freely filtered by the glomeruli. Seventy to 80% of the filtered Na" load is then actively reabsorbed in the proximal tubules, with 01 and water passively following in an isoosmotic and electrically neutral manner. Another 20% to 25% is reabsorbed in the loop of Henle along with Cl" and more water. In the distal tubules, interaction of the adrenal hormone aldosterone with the coupled Na -K and Na -H exchange systems directly results in the reabsorption of Nah and indirectly of d , from the remaining 5% to 10% of the filtered load. It is the regulation of this latter fraction of filtered Na that primarily determines the amount of Na excreted in the urine. These processes are discussed in detail in Chapter 45. 

Yoshizumi, M. et al.. Mechanism of palytoxin-induced Na influx into cultured bovine adrenal chromaffin cells possible involvement of Na /H exchange system, Neurosci. Lett. 130, 103, 1991. 

Ghosh P, Wellner R, Cragoe E, Wu H. Enhacement of ricin cytotoxicity in Chinese hamster ovary cells by depletion of intracellular K+ Evidence for Na+/H+ exchange system in Chinese hamster ovary cells. J Cell Biol. 1985 101 350-357. 

One mode of Ca " release is manifested in a Ca -nH exchange [130-132]. Experimentally this system can function bidirectionally, but presumably in the cell the extramitochondrial pH is always lower than the intramitochondrial pH so that in vivo this exchange system catalyses Ca efflux. Similarly, the Na -dependent Ca flux found in mitochondria from some tissues [129,133] will be outwardly directed in the cell, since extramitochondrial Na is higher than intramitochondrial Na" due to the presence of a Na -H" exchange system. It is tempting to think that the Na" -dependent pathway for Ca " flux is actually a combination of the Na -H and the Ca -nH" exchange systems, but this does not appear to be likely [129]. 

Sodium bicarbonate reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger located in the luminal membrane of the proximal tubule epithelial cell (Figure 15-3). This transport system allows sodium to enter the cell from the tubular lumen in exchange for a proton from inside the cell. As in all portions of the nephron, Na+/K+ ATPase in the basolateral... 

The Na+/H+ exchanger is usually considered to catalyze the exchange of Na+ for H+. It should be noted, however, that because the kinetics of H+ binding are identical to the kinetics of OH de-binding (by virtue of the small dissociation constant of water), it cannot be determined whether the system acts as an Na+/H+ exchanger or as an Na+/OH cotransporter. 

It was first demonstrated by Aronson et al. (1982) that internal H+ stimulates the net influx of Na+ with sigmoidal kinetics rather than with classical Michaelis-Men-ten kinetics. Such a cooperative interaction of internal H+ with the Na+/H+ exchanger has been found in most cell types with apparent values of the Hill coefficient ranging from 1.2 to almost 3. A cooperative interaction of internal H+ allows the system to respond rather markedly to a small variation in pHi. This property is ideal for a fine tuning of the pHi. 

In some cells, short-term activation of Na+/H+ exchange involves an increase in maximum velocity of the system. The molecular mechanism underlying this regulation has not yet been elucidated. 

Slow (adaptative) changes in Na+/H+ exchange activity have been observed in response to several hormonal effectors under pathological situations (Sacktor and Kinsella, 1988). These actions are mediated by changes either in the kinetic properties of the system or in the number of functional exchangers. 

Three types of transport mechanisms for bicarbonate have been identified (a) an electroneutral Na+ dependent Cr/HCO cotransporter (b) an electroneutral, Na+ independent Cl /HCO cotransporter and (c) an electrogenic NaVHCOj n (n>l) cotransporter. Unlike the Na+/H+ exchanger which is ubiquitous, bicarbonate transport mechanisms are expressed in a cell specific manner. In most cell types, however, the Na+/H+ exchanger coexists with one or several bicarbonate transport systems. As a consequence, pHi regulation can be achieved by various means in different cell types. 

As in the case of the Na+/H+ exchanger, the activity of bicarbonate transport systems is regulated by both protein kinase A and protein kinase C (Vigne et al., 1988 Ganz et al., 1989). 

At least three types of proton channel systems are recognized in animal cells. These include the Na+/H+ exchanger, the H+-ATPase, and the HCOj/Cl- exchanger. It is clear that a major part of proton release by some cells in response to transplasma membrane electron transport is by activation of the Na+/H+ exchanger. This is clear from the characteristics of the proton movement elicited and the magnitude of H+ release in relation to electron flow when electron transport is activated. Activation of electron transport can be elicited by addition of di-ferric transferrin to activate the transmembrane NADH oxidase activity or by electron flow to external ferricyanide from internal NADH. Addition of di-ferric transferrin to certain cells, especially pineal cells, elicits a remarkable proton release and internal alkaliniza-tion. The stoichiometry of H+ release to iron reduced is more than 100 to 1 (Sun et... 

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). 

The electrical activity of the heart is modulated by hormones and neurotransmitters. Xenobiotics disturb their balance. The parasympathetic system releases ACh and the sympathetic system releases catecholamines (norepinephrine and epinephrine). These bind to a and p types of receptors. ai-receptors are present on the post-synaptic member of the organ and mediate vasoconstriction and stimulation of Na" /K -ATPase, the Na" /Ca exchanger, and the Na /H exchanger. This affects the Ikatp and inhibits the Ij,ia+ and Ito. The a-receptor stimulation thus effectuates depolarization, and the a2-receptor inhibits norepinephrine release. 

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