Na+/H+ Antiport
Acid Vesicles

Author: Gianpiero Pescarmona
Date: 24/01/2010



The mammalian NHE is a ubiquitously expressed integral membrane protein that regulates intracellular pH by removing a proton in exchange for an extracellular sodium ion.
They belong to the group of the solute carrier (SLC) group of membrane transport proteins that includes over 300 members organized into 47 families. A number of bacterial NHEs is also described and characterized.

There are many isoforms. The more studied are:

Entrez Gene"SLC9A1":"SLC9A3":
OMIM Gene map"SLC9A1":"SLC9A3":


When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure


mRNA synthesis
protein synthesis
post-translational modifications


cellular localization,
biological function

Structural and functional analysis of the Na+/H+ exchanger. 2007

Of the nine known isoforms of the mammalian NHEs, the first isoform discovered (NHE1) is the most thoroughly characterized. NHE1 is involved in numerous physiological processes in mammals, including regulation of intracellular pH, cell-volume control, cytoskeletal organization, heart disease and cancer. NHE comprises two domains: an N-terminal membrane domain that functions to transport ions, and a C-terminal cytoplasmic regulatory domain that regulates the activity and mediates cytoskeletal interactions. Although the exact mechanism of transport by NHE1 remains elusive, recent studies have identified amino acid residues that are important for NHE function. In addition, progress has been made regarding the elucidation of the structure of NHEs. Specifically, the structure of a single TM (transmembrane) segment from NHE1 has been solved, and the high-resolution structure of the bacterial Na+/H+ antiporter NhaA has recently been elucidated. In this review we discuss what is known about both functional and structural aspects of NHE1. We relate the known structural data for NHE1 to the NhaA structure, where TM IV of NHE1 shows surprising structural similarity with TM IV of NhaA, despite little primary sequence similarity. Further experiments that will be required to fully understand the mechanism of transport and regulation of the NHE1 protein are discussed.

  • Enzymes
  • Cell signaling and Ligand transport
  • Structural proteins


Cardiac glycoside downregulates NHE3 activity and expression in LLC-PK1 cells. 2005
Am J Physiol Renal Physiol. 2006 May;290(5):F997-1008. Epub 2005 Dec 13.

  • Ouabain, a cardiotonic steroid and a specific inhibitor of the Na(+)-K(+)-ATPase, has been shown to significantly inhibit transcellular Na(+) transport without altering the intracellular Na(+) concentration ([Na(+)](i)) in the epithelial cells derived from the renal proximal tubules. We therefore studied whether ouabain affects the activity and expression of Na(+)/H(+) exchanger isoform 3 (NHE3) representing the major route of apical Na(+) reabsorption in LLC-PK cells. Chronic basolateral, but not apical, exposure to low-concentration ouabain (50 and 100 nM) did not change [Na(+)](i) but significantly reduced NHE3 activity, NHE3 protein, and mRNA expression. Inhibition of c-Src or phosphoinositide 3-kinase (PI3K) with PP2 or wortmannin, respectively, abolished ouabain-induced downregulation of NHE3 activity and mRNA expression. In caveolin-1 knockdown LLC-PK cells, ouabain failed to downregulate NHE3 mRNA expression and NHE3 promoter activity. Ouabain response elements were mapped to a region between -450 and -1,194 nt, where decreased binding of thyroid hormone receptor (TR) and Sp1 to their cognate cis-elements was documented in vitro and in vivo by protein/DNA array analysis, EMSA, supershift, and chromatin immunoprecipitation. These data suggest that, in LLC-PK cells, ouabain-induced signaling through the Na(+)-K(+)-ATPase-Src pathway results in decreased Sp1 and TR DNA binding activity and consequently in decreased expression and activity of NHE3. These novel findings may represent the underlying mechanism of cardiotonic steroid-mediated renal compensatory response to volume expansion and/or hypertension.


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