Physiological Role of Na+/H+ Exchange in Epithelial Cells

The concept that a process of Na⁺ for H⁺ exchange plays a role in the transepithelial transport of acid-base equivalents dates back to at least the 1940s. ¹ However, it was not until nearly 30 years later that direct evidence for a Na⁺/H⁺ exchanger was presented, ² based on work on luminal membrane vesicles of the rat proximal tubule and intestine. Since then, transport systems that mediate the exchange of Na⁺ for H⁺ across the plasma membrane have been identified in a wide variety of epithelial and nonepithelial cells. ^{3 , 4} Epithelial cells possessing a Na⁺/H⁺ exchanger include several renal-tubule cells, intestinal and gall bladder cells, and a variety of epithelial cells in culture. ⁵ Under normal conditions, the Na⁺/H⁺ exchanger energizes the uphill extrusion of H⁺ from the cell by coupling this flux to the downhill entry of Na⁺. The favorable electrochemical gradient for Na⁺ entry is in turn maintained by the active transport of Na⁺ out of the cell by the Na/K pump, fueled by ATP hydrolysis. Thus, the Na/K pump is an example of primary active transport, and the Na⁺/H⁺ exchanger, of secondary active transport. Perhaps the most striking characteristic of the Na⁺/H⁺ exchanger is its sensitivity to the diuretic amiloride ^{6 , 7} and several more potent amiloride analogues. ⁸ Kinetic studies have shown that amiloride is a simple competitor with respect to external Na⁺, ⁹ and that the exchanger has an appreciable affinity for Li⁺ and NH 4 + https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781351074889/d386649a-919c-4672-a203-15fea85f494f/content/eq129.tif"/> . ¹⁰ The direction of net exchange can be reversed by reversing the sum of the gradients for Na⁺ and H⁺. Finally, this transporter has a characteristic pH_i dependence ¹¹ which causes the exchanger to be inactive at pH_i values above a certain threshold and then to gradually activate as pH_i falls below this pH_i threshold. The basis for this pH_i dependence is probably an internal H⁺ modifier site, for which kinetic evidence has been presented. ¹²