OBJECTIVE 2: TO DETERMINE THE MECHANISMS INVOLVED IN PROTON SECRETION.

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A. In the proximal tubule the major mechanisms involved in proton secretion are the Na-H exchanger in the apical membrane and the Na-HCO₃ cotransporter in the basolateral membrane (Fig. 9-2a). The Na-H exchanger extrudes protons from the cell against the chemical gradient. The rate of secretion is gradient-limited. An increase in the proton gradient across the apical membrane reduces secretion. In the proximal tubule the limiting gradient at which net secretion is stopped is reached at a tubular fluid pH of about 6.8 in the rat and about 7.2 in the dog. The Na-HCO3 cotransporter in the basolateral membrane is electrogenic; it transports one cation and 3 anions. The primary driving force for this mechanism is the electrical gradient across the basolateral membrane.

An increase in proton concentration in the cytoplasm, in addition to its effect on the gradients driving the transporter, causes the insertion of additional exchanger units into the apical membrane, increasing the rate of secretion. The Na-H exchanger can be blocked by high concentrations of amiloride, concentrations too high to be of use for other than experimental purposes. The exchanger is also present in the thick ascending limb and in the early distal tubule.

Fig. 9-2A. Na-H exchanger and Na-HCO₃ cotransporter in proximal tubule.

Fig. 9-2B. Proton ATPase, Cl-HCO₃ exchanger and Cl channel in intercalated cells.

Fig. 9-2C.  H-K exchanger in intercalated cells.

B. A proton ATPase pump, a primary active transport system, exists in the apical membrane of α-intercalated cells in the late distal tubule and in the collecting tubule (fig. 9-2B). It is also present to some extent in late sections of the proximal tubule. HCO₃ generated within the cell as a result of the fall in proton concentration is transported out of intercalated cells by a neutral Cl:HCO₃ exchanger in the basolateral membrane. The Cl, which is transported into the cell, cycles back into the ISF via a chloride channel.

1. This electrogenic proton pump is also gradient-limited. The transport of protons into the tubular fluid raises the concentration there and hyperpolarizes the apical membrane. This electrochemical gradient opposing the pump slows it down. The limiting gradient in the collecting duct is reached when the tubular fluid pH approaches 4.5. This corresponds to a transepithelial gradient of about 800:1 for proton concentration.

2. A fall in cell pH or a rise in cell P_CO2 causes the insertion of additional pump units into the membrane thus increasing the secretory capacity of the cells.

C. Another proton ATPase, one that exchanges protons for K ions, is also present in the apical membrane of -intercalated cells in the late distal tubule and collecting duct. This transporter is electrically neutral and is not affected by the electrical gradient across the apical membrane.

QUESTIONS:  
3. How are each of the three proton secretory mechanisms affected by the apical membrane potential? How and to what extent are the Na-H exchanger and the proton ATPase affected by the proton chemical gradient across the apical membrane?

4. The secretion of protons leads to an accumulation of HCO₃ within the cells. How do the proximal tubular cells handle that? How do the -intercalated cells handle it? The HCO₃ concentration within the cells is less than that in interstitial fluid. What forces drive the exit of HCO₃ in the two types of cells?

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