The Changing Face of the Na+/H+ Exchanger, NHE1: Structure, Regulation, and Cellular Actions

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Abstract
▪ Abstract The NHE family of ion exchangers includes six isoforms (NHE1–NHE6) that function in an electroneutral exchange of intracellular H+ for extracellular Na+. This review focuses on the only ubiquitously expressed isoform, NHE1, which is localized at the plasma membrane where it plays a critical role in intracellular pH (pHi) and cell volume homeostasis. All NHE isoforms share a similar topology: an N-terminus of 12 transmembrane (TM) α-helices that collectively function in ion exchange, and a C-terminal cytoplasmic regulatory domain that modulates transport activity by the TM domain. Extracellular signals, mediated by diverse classes of cell-surface receptors, regulate NHE1 activity through distinct signaling networks that converge to directly modify the C-terminal regulatory domain. Modifications in the C-terminus, including phosphorylation and the binding of regulatory proteins, control transport activity by altering the affinity of the TM domain for intracellular H+. Recently, it was determined ...