Calcium-sensing receptor deletion in the mouse esophagus alters barrier function.
Calcium-sensing receptor (CaSR) is the molecular sensor by which cells respond to small changes in extracellular Ca2+ concentrations. CaSR has been reported to play a role in glandular and fluid secretion in the gastrointestinal tract and to regulate differentiation and proliferation of skin keratinocytes. CaSR is present in the esophageal epithelium, but its role in this tissue has not been defined. We deleted CaSR in the mouse esophagus by generating keratin 5 CreER;CaSRcompound mutants, in which loxP sites flank exon 7 of CaSR gene. Recombination was initiated with multiple tamoxifen injections, and we demonstrated exon 7 deletion by PCR analysis of genomic DNA. Quantitative real-time PCR and Western blot analyses showed a significant reduction in CaSR mRNA and protein expression in the knockout mice () as compared with control mice. Microscopic examination of  esophageal tissues showed morphological changes including elongation of the rete pegs, abnormal keratinization and stratification, and bacterial buildup on the luminal epithelial surface. Western analysis revealed a significant reduction in levels of adherens junction proteins E-cadherin and β catenin and tight junction protein claudin-1, 4, and 5. Levels of small GTPase proteins Rac/Cdc42, involved in actin remodeling, were also reduced. Ussing chamber experiments showed a significantly lower transepithelial resistance in knockout (KO) tissues. In addition, luminal-to-serosal-fluorescein dextran (4 kDa) flux was higher in KO tissues. Our data indicate that CaSR plays a role in regulating keratinization and cell-cell junctional complexes and is therefore important for the maintenance of the barrier function of the esophagus.NEW & NOTEWORTHY The esophageal stratified squamous epithelium maintains its integrity by continuous proliferation and differentiation of the basal cells. Here, we demonstrate that deletion of the calcium-sensing receptor, a G protein-coupled receptor, from the basal cells disrupts the structure and barrier properties of the epithelium.
['Nakhoul|Nazih L|NL|', 'Tu|Chia-Ling|CL|', 'Brown|Karen L|KL|', 'Islam|M Toriqul|MT|', 'Hodges|Anna G|AG|', 'Abdulnour-Nakhoul|Solange M|SM|0000-0001-9553-6438']
D022005:Adherens Junctions D000818:Animals D015820:Cadherins D002454:Cell Differentiation D049109:Cell Proliferation D057167:Claudins D017097:Electric Impedance D000071041:Esophageal Mucosa D005260:Female D017353:Gene Deletion D008297:Male D018345:Mice, Knockout D010539:Permeability D044169:Receptors, Calcium-Sensing D015398:Signal Transduction D019108:Tight Junctions D051176:beta Catenin D020764:cdc42 GTP-Binding Protein D020744:rac GTP-Binding Proteins
keratinization adherens junctions tight junction stratified squamous epithelium bacteria calcium sensing claudin GPCR