Sodium/Proton Exchange Mechanisms in Epithelial Cells

Epithelial cells line the surfaces and cavities of organs, where they regulate ion transport and fluid balance. Central to this function are sodium/proton exchangers (NHEs), transmembrane proteins that mediate the electroneutral exchange of extracellular sodium ions for intracellular protons. By controlling intracellular pH and sodium uptake, NHEs influence cell volume, nutrient absorption and acid–base homeostasis. Multiple isoforms localise either to the apical membrane, such as NHE3 in renal and intestinal epithelia, or to intracellular compartments, including endosomes and the Golgi network. Regulation of exchanger activity occurs through phosphorylation, interaction with scaffolding proteins and hormonal signals, enabling rapid responses to changes in luminal pH, dietary intake or circulating mediators. Dysregulation of NHE function contributes to disorders ranging from diarrhoeal disease and hypertension to inherited syndromes affecting neural development. Advances in high-resolution imaging, organoid culture and computational modelling have deepened our understanding of isoform-specific roles and opened avenues for targeted therapies in gastrointestinal and renal pathologies.

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Sodium/Proton Exchange Mechanisms in Epithelial Cells publication trend

The graph below shows the total number of articles in sodium/proton exchange mechanisms in epithelial cells across all publications each year (not limited to Nature Index journals).

Technical terms

Na+/H+ exchanger (NHE): A membrane protein that swaps extracellular sodium ions for intracellular protons, crucial for pH regulation and sodium uptake.

Isoform: A variant form of a protein arising from gene duplication or alternative splicing, often with distinct localisation or regulation.

Apical membrane: The cell surface of an epithelial cell facing the lumen or external environment, where specific transporters mediate exchange with the contents.

Transepithelial electrical resistance (TEER): A measure of barrier integrity across an epithelial layer, reflecting tight junction tightness and ionic permeability.

Physiologically based biopharmaceutics model (PBBM): A computational framework that simulates drug absorption, distribution and interaction with physiological processes to predict in vivo behaviour.

Colonoid: A three-dimensional culture derived from human colonic crypts that recreates key features of intestinal epithelial organisation and function.

References

1. Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract—Case Study: Tenapanor. Pharmaceutics (2023).
2. Human Colonoid–Myofibroblast Coculture for Study of Apical Na+/H+ Exchangers of the Lower Cryptal Neck Region. International Journal of Molecular Sciences (2023).
3. Four Na+/H+ Exchanger Isoforms Are Distributed to Golgi and Post-Golgi Compartments and Are Involved in Organelle pH Regulation*. Journal of Biological Chemistry (2004).
4. Activation of Na+/H+ Exchanger NHE3 by Angiotensin II Is Mediated by Inositol 1,4,5-Triphosphate (IP3) Receptor-binding Protein Released with IP3 (IRBIT) and Ca2+/Calmodulin-dependent Protein Kinase II*. Journal of Biological Chemistry (2010).
5. An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease. Frontiers in Cellular Neuroscience (2014).
6. Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome. CNS Neuroscience & Therapeutics (2023).