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Cited by 32Ion Transport and Channel RegulationDigestive system and related healthDrug Transport and Resistance Mechanisms

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

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Nikolovska, Katerina, Seidler, Ursula E., Stock, Christian·2022·Frontiers in Physiology
DOI 10.3389/fphys.2022.899286PMC PMC9159811
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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 pH i 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.

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  • NHE3 exchanges one luminal Na ion for one intracellular H ion and is the principal NHE isoform expressed in the small intestinal brush border membrane.

    “NHE3 exchanges one luminal Na ion for one intracellular H ion and is the principal NHE isoform expressed in the small intestinal BBM [20].”

    From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [20]

    The small-intestine crypt–villus diagram caption identifies NHE3 as the major brush-border NHE isoform responsible for Na+ absorption. The NHE3 expression section describes apical Na+/H+ exchange, but the passages found do not specify that it exchanges exactly one luminal Na+ for one intracellular H+. (LLM, conf=0.84)

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Authors
Nikolovska, K., Seidler, U. E., & Stock, C.
Affiliations
Medizinische Hochschule Hannover (DE)
Corresponding author
Stock, Christian
ORCID
Venue
Frontiers in Physiology
Publisher
Frontiers Media SA
Published
2022-05-18
Volume
13
Pages
899286-899286
ISSN
1664-042X (ISSN-L)
DOI
10.3389/fphys.2022.899286
PMC
PMC9159811
OpenAlex
W4280516288
Cited by
32
References
0
Citations by year
2026: 7 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 2
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
NHE isoforms, NHE1, NHE2, NHE3, NHE8, intestinal epithelial cells, intestinal barrier integrity, intestinal homeostasis, parietal cells, acid secretion, cell volume regulation, intestinal organoids

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