Sodium-Proton (Na⁺/H⁺) Antiporters: Properties and Roles in Health and Disease

The transmembranal Na⁺/H⁺ antiporters transport sodium (or several other monovalent cations) in exchange for H⁺ across lipid bilayers in all kingdoms of life. They are critical in pH homeostasis of the cytoplasm and/or organelles. A particularly notable example is the SLC9 gene family, which encodes Na⁺/H⁺ exchangers (NHEs) in many species from prokaryotes to eukaryotes. In humans, these proteins are associated with the pathophysiology of various diseases. Yet, the most extensively studied Na⁺/H⁺ antiporter is Ec-NhaA, the main Na⁺/H⁺ antiporter of Escherichia coli. The crystal structure of down-regulated Ec-NhaA, determined at acidic pH, has provided the first structural insights into the antiport mechanism and pH regulation of an Na⁺/H⁺ antiporter. It reveals a unique structural fold (called the NhaA fold) in which transmembrane segments (TMs) are organized in inverted-topology repeats, including two antiparallel unfolded regions that cross each other, forming a delicate electrostatic balance in the middle of the membrane. This unique structural fold (The NhaA fold) contributes to the cation binding site and facilitates the rapid conformational changes expected for Ec-NhaA. The NhaA fold has now been recognized to be shared by four Na⁺/H⁺ antiporters (bacterial and archaeal) and a Na⁺ symporter. Remarkably, no crystal structure of any of the human Na⁺/H⁺ antiporters exists. Nevertheless, the Ec-NhaA crystal structure has enabled the structural modeling of NHE1, NHE9, and NHA2, three human plasmalemmal proteins that are members of the SLC9 family that are involved in human pathophysiology. Moreover, as outlined in this review, developments in the field, including cellular and biophysical methods that enable ion levels and fluxes to be measured in intact cells as well as in knockout mice, have led to striking advances in the identification and characterization of plasma membrane NHEs and NHA. Very little is known about the endomembrane isoforms of NHE. These intracellular exchangers may serve a function in cation homeostasis and/or osmoregulation, and not in pH regulation as is the case for the plasmalemmal isoforms. This intriguing possibility should be borne in mind when designing future studies Future progress towards gaining an understanding of the SLC9 gene family, including its structure-function relationships and regulatory mechanisms in health and in disease, is likely to include insights into the pathophysiology of multiple diseases.