Acute Regulation of Proximal Tubule Apical Membrane Na/H Exchanger NHE-3

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Abstract
Mammalian Na/H exchangers (NHE) are ubiquitous membrane ion transporters belonging to a gene family of related proteins that utilize a downhill transmembrane Na+ gradient to energize H+ extrusion up an electrochemical gradient in an electroneutral 1:1 stoichiometry. Although Na+ follows first order Michaelis-Menton kinetics (7,8), intracellular H+ serves as a substrate as well as an allosteric activator (9). The seminal paper by Sardet and coworkers describes the cloning of the first NHE isoform using an elegant genetic complementation approach (10). Based on the first cDNA, a total of six members of this gene family has been identified in mammals thus far (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24). In addition, piscine, crustacean, and prokaryotic homologues exist with variable structural and functional similarities to the mammalian exchangers (25, 26, 27, 28, 29, 30). The different mammalian NHE isoforms have distinct pharmacokinetic characteristics, regulatory mechanisms, and tissue and cellular distributions. Several excellent recent general reviews are available (31, 32, 33, 34). The primary amino acid sequence of the NHE predicts a putative topology of the transporter protein as shown in Figure 1. An amino terminus transmembrane domain of approximately 400 amino acids performs Na/H exchange function, and a carboxy terminus cytoplasmic domain receives and interacts with incoming regulatory signals and exerts control over the transmembrane transporting domain. Although the current paradigm of the structural and functional domains are largely correct, the truth is likely more complex than the model of a strictly bipartite functional and structural division. Biemesderfer et al. propose that while the carboxy-terminal domain may be largely cytoplasmic, the carboxy-terminal tail may actually be extracellular (35). It is currently unknown how the cytoplasmic tail with virtually no hydrophobic regions can traverse the lipid bilayer. From the functional standpoint, in contrast to the NHE-1 isoform (36), the region of the molecule responsible for acute regulation of NHE-3 by hypertonicity likely resides in the transmembrane rather than the cytoplasmic domain (37,38).

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