The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

Abstract

The five plasma membrane Na+/H+ exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis. They are involved in pHi regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na+ absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na+/H+ exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract.

SLC9A2, suppressing by the transcription suppressor ETS1, restrains growth and invasion of osteosarcoma via inhibition of aerobic glycolysis

“…31 Currently, research has found that SLC9A2 is not only expressed in gastrointestinal epithelial cells, but also expressed in kidney, endometrium and chondrocytes. 30 A few of studies have shown that SLC9A2 can be used as a potential we attested for the first time that SLC9A2 could curb the proliferation and invasion of OS cells. Therefore, it is necessary to investigate the mechanism of SLC9A2 in OS.…”

“…The encoded protein is localized to the apical membrane and is easily degraded by lysosomes, resulting in a short half-life. 30 SLC9A2 is involved in sodium ion transport by exchanging intracellular hydrogen ions into external sodium ions, and helps in the regulation of cell pH and volume to eliminate acids produced by active metabolism or against adverse environmental conditions. 31 Currently, research has found that SLC9A2 is not only expressed in gastrointestinal epithelial cells, but also expressed in kidney, endometrium and chondrocytes.…”

“…It mainly encodes a member of the sodium‐hydrogen exchanger (NHE) protein family. The encoded protein is localized to the apical membrane and is easily degraded by lysosomes, resulting in a short half‐life 30 . SLC9A2 is involved in sodium ion transport by exchanging intracellular hydrogen ions into external sodium ions, and helps in the regulation of cell pH and volume to eliminate acids produced by active metabolism or against adverse environmental conditions 31 .…”

“…SLC9A2 is involved in sodium ion transport by exchanging intracellular hydrogen ions into external sodium ions, and helps in the regulation of cell pH and volume to eliminate acids produced by active metabolism or against adverse environmental conditions 31 . Currently, research has found that SLC9A2 is not only expressed in gastrointestinal epithelial cells, but also expressed in kidney, endometrium and chondrocytes 30 . A few of studies have shown that SLC9A2 can be used as a potential biomarker for cancers 32–34 .…”

Single-cell transcriptomic mapping of intestinal epithelium that undergoes 3D morphogenesis and mechanodynamic stimulation in a gut-on-a-chip

“…For instance, NHE2 is expressed in the crypts in mice or on the whole surface of the villus or upper half of the colonic crypt in rabbits. 51 , 52 Yet, no published report shows the expression of NHE2 in the human intestine. At the mRNA level, however, NHE2 is expressed throughout the vertical axis of the crypt in the human colon.…”