Beyond ion translocation: structural functions of the sodium–hydrogen exchanger isoform-1

Abstract

The sodium-hydrogen exchanger isoform-1 (NHE1) functions in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Recent studies have revealed the structural functions of NHE1 as an anchor for actin filaments and a scaffold for an ensemble of signaling proteins. This review highlights how these functions contribute to NHE1 regulation of biochemical events and cell behaviors. New data confirming nontransport structural functions of NHE1 suggest reexamining how NHE1 regulates cell functions. Cell survival, cell substrate adhesion, and organization of the actin cytoskeleton are confirmed to be regulated through actin anchoring by NHE1 and likely by NHE1-dependent scaffolding of signaling proteins. A role for NHE1 in mechanotransduction is emerging and a challenge of future studies is to determine whether structural functions of NHE1 are important for mechanoresponsiveness. This review highlights evidence for the nontransport functions of NHE1 and describes how the structural functions are integrated with ion translocation to regulate a range of cellular processes. Nontransporting features of NHE1 are analogous to recently observed nonconducting actions of ion channels in regulating cell behaviors and represent an emerging paradigm of ion transporters as multifunctional proteins.