Expression of calcium-sensing receptor in rat colonic epithelium: evidence for modulation of fluid secretion

Abstract

The calcium-sensing receptor (CaSR) is activated by extracellular calcium (Ca2+(o)) and mediates many of the known effects of extracellular divalent minerals on body cells. Both surface and crypt cells express CaSR transcripts and protein on both apical and basolateral surfaces. Raising Ca2+(o) elicited increases in intracellular calcium (Ca2+(o)) in both surface and crypt cells with an EC50 of 2 mM. The Ca-induced increase in Ca2+(i) was associated with increases in inositol 1,4,5-trisphosphate and eliminated by U-73129, an inhibitor of phosphatidylinositol-phospholipase C, as well as by thapsigargin. Other CaSR agonists, Gd3+ and neomycin, mimicked these Ca2+(o)-induced responses. Both luminal and bath Ca2+(o), Gd3+, and neomycin induced increases in Ca2+(i) in isolated perfused crypts. The stimulatory effect of forskolin on net fluid secretion in perfused crypts was abolished by increasing Ca2+(o) in either luminal or bath perfusates. Thus both apical and basolateral CaSR on crypt cells are functional and provide pathways modulating net intestinal fluid transport that may have important implications for the prevention and treatment of certain diarrheal diseases associated with elevated cAMP.

Calcium-sensing receptor stimulates Cl−- and SCFA-dependent but inhibits cAMP-dependent HCO3− secretion in colon

“…The CaSR is widely expressed in the gastrointestinal tract, including the epithelial cells that line the entire small and large intestine (9,14,16,23) and regulate ion and fluid transport, thus raising the possibility that these receptors may have important roles in regulation of intestinal fluid and electrolyte movement in both health and disease. In enteric epithelial cells, CaSR has been identified on both the apical and basolateral membranes of human (16,44) and rat colonocytes (9,16).…”

The extracellular calcium-sensing receptor (CaSR) on human esophagus and evidence of expression of the CaSR on the esophageal epithelial cell line (HET-1A)

“…Definitive evidence for CaSR expression in the mammalian esophagus has been lacking. The CaSR is expressed in mammalian stomach (11), small intestine, and colon (7,9,12,13,17). In the stomach, CaSR activation has been shown to increase gastrin release and H ϩ secretion (18), whereas, in the colon, CaSR activation reduces forskolinstimulated fluid secretion (19).…”

The extracellular calcium-sensing receptor reciprocally regulates the secretion of BMP-2 and the BMP antagonist Noggin in colonic myofibroblasts

“…Evidence about the CaSR's physiological role in the gut is limited to the colon, where its activation by either Ca o 2ϩ or spermine inhibits forskolin-stimulated secretion (9,10). High Ca 2ϩ has been shown to inhibit ␤-catenin signaling on colonic cancer cell lines (7), and expression of the colonic CaSR is progressively lost during the transition from adenoma to carcinoma (7,41).…”