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Calcium-sensing receptor deletion in the mouse esophagus alters barrier function
Nazih L Nakhoul1,2, Chia-Ling Tu3, Karen L Brown1,2
1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
American Journal of Physiology. Gastrointestinal and Liver Physiology
|November 12, 2019
Summary
The calcium-sensing receptor (CaSR) is crucial for esophageal barrier function. Its deletion disrupts keratinization and cell junctions, impairing esophageal integrity and increasing permeability.
Area of Science:
- Gastroenterology
- Cell Biology
- Molecular Biology
Background:
- The calcium-sensing receptor (CaSR) detects extracellular calcium and influences various cellular processes.
- CaSR's role in the esophageal epithelium, particularly in barrier function, remains largely undefined.
- The esophageal stratified squamous epithelium relies on basal cell proliferation and differentiation for integrity.
Purpose of the Study:
- To investigate the role of CaSR in the mouse esophageal epithelium.
- To determine the impact of CaSR deletion on esophageal structure and barrier function.
Main Methods:
- Generated keratin 5 CreER;CaSR compound mutant mice for conditional CaSR deletion in the esophagus.
- Confirmed CaSR gene deletion via PCR and assessed mRNA/protein expression using qRT-PCR and Western blot.
- Analyzed esophageal tissue morphology, cell-cell junction protein levels (E-cadherin, β-catenin, claudins), and GTPase signaling (Rac/Cdc42).
- Evaluated barrier function using Ussing chamber experiments measuring transepithelial resistance and fluorescein dextran flux.
Main Results:
- CaSR deletion in esophageal basal cells led to significant morphological changes, including abnormal keratinization and stratification.
- Levels of key adherens junction (E-cadherin, β-catenin) and tight junction (claudin-1, -4, -5) proteins were reduced.
- Transepithelial electrical resistance was significantly lower, and paracellular permeability (flux) was higher in CaSR-deficient esophageal tissues.
- Reduced levels of Rac/Cdc42 GTPases suggest impaired actin remodeling.
Conclusions:
- CaSR is essential for maintaining esophageal epithelial integrity and barrier function.
- CaSR regulates keratinization and the formation/maintenance of cell-cell junctional complexes in the esophagus.
- Disruption of CaSR signaling compromises esophageal structural integrity and barrier properties, potentially increasing susceptibility to luminal contents.
