Open AccessCytoskeletal changes induced by allosteric modulators of calcium‐sensing receptor in esophageal epithelial cells
Author(s) -
AbdulnourNakhoul Solange,
Brown Karen L.,
Rabon Edd C.,
AlTawil Youhanna,
Islam Mohammed T.,
Schmieg John J.,
Nakhoul Nazih L.
Publication year - 2015
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12616
Subject(s) - calcium sensing receptor , cell growth , receptor , microbiology and biotechnology , chemistry , cell , cell migration , cytoskeleton , biology , cancer research , endocrinology , medicine , calcium , calcium metabolism , biochemistry
The calcium‐sensing receptor (Ca SR ), a G‐protein‐coupled receptor, plays a role in glandular and fluid secretion in the gastrointestinal tract, and regulates differentiation and proliferation of epithelial cells. We examined the expression of Ca SR in normal and pathological conditions of human esophagus and investigated the effect of a Ca SR agonist, cinacalcet ( CCT ), and antagonist, calhex ( CHX ), on cell growth and cell–cell junctional proteins in primary cultures of porcine stratified squamous esophageal epithelium. We used immunohistochemistry and Western analysis to monitor expression of Ca SR and cell–cell adhesion molecules, and MTT assay to monitor cell proliferation in cultured esophageal cells. CCT treatment significantly reduced proliferation, changed the cell shape from polygonal to spindle‐like, and caused redistribution of E‐cadherin and β ‐catenin from the cell membrane to the cytoplasm. Furthermore, it reduced expression of β ‐catenin by 35% ( P < 0.02) and increased expression of a proteolysis cleavage fragment of E‐cadherin, Ecad/ CFT 2, by 2.3 folds ( P < 0.01). On the other hand, CHX treatment enhanced cell proliferation by 27% ( P < 0.01), increased the expression of p120‐catenin by 24% ( P < 0.04), and of Rho, a GTP ase involved in cytoskeleton remodeling, by 18% ( P < 0.03). In conclusion, Ca SR is expressed in normal esophagus as well as in Barrett's, esophageal adenocarcinoma, squamous cell carcinoma, and eosinophilic esophagitis. Long‐term activation of Ca SR with CCT disrupted the cadherin–catenin complex, induced cytoskeletal remodeling, actin fiber formation, and redistribution of Ca SR to the nuclear area. These changes indicate a significant and complex role of Ca SR in epithelial remodeling and barrier function of esophageal cells.