title: Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon.
abstract: Colonic bicarbonate (HCO3(-)) secretion is a well-established physiological process that is closely linked to overall fluid and electrolyte movement in the mammalian colon. These present studies show that extracellular calcium-sensing receptor (CaSR), a fundamental mechanism for sensing and regulating ionic and nutrient compositions of extracellular milieu in the small and large intestine, regulates HCO3(-) secretion. Basal and induced HCO3(-) secretory responses to CaSR agonists were determined by pH stat techniques used in conjunction with short-circuit current measurements in mucosa from rat distal colon mounted in Ussing chambers. R568, a specific CaSR activator, stimulated lumen Cl(-)- and short-chain fatty acid (SCFA)-dependent HCO3(-) secretion but inhibited cyclic nucleotide-activated HCO3(-) secretion. Consequently, at physiological conditions (either at basal or during lumen acid challenge) when electroneutral Cl(-)/HCO3(-) and SCFA/HCO3(-) exchangers dominate, CaSR stimulates HCO3(-) secretion; in contrast, in experimental conditions that stimulate fluid and HCO3(-) secretion, e.g., when forskolin activates electrogenic cystic fibrosis transmembrane conductance regulator-mediated HCO3(-) conductance, CaSR activation inhibits HCO3(-) secretion. Corresponding changes in JHCO3 (μeq·h(-1)·cm(-2), absence vs. presence of R568) were 0.18 ± 0.03 vs. 0.31 ± 0.08 under basal nonstimulated conditions and 1.85 ± 0.23 vs. 0.45 ± 0.06 under forskolin-stimulated conditions. Similarly, activation of CaSR by R568 stimulated Cl(-)- and SCFA-dependent HCO3(-) secretion and inhibited cAMP-dependent HCO3(-) secretion in colon mucosa of wild-type mice; such effects were abolished in CaSR-null mice. These results suggest a new paradigm for regulation of intestinal ion transport in which HCO3(-) secretion may be fine-tuned by CaSR in accordance with nutrient availability and state of digestion and absorption. The ability of CaSR agonists to inhibit secretagogue-induced intestinal HCO3(-) secretion suggests that modulation of CaSR activity may provide a new therapeutic approach to correct HCO3(-) deficit and metabolic acidosis, a primary cause of morbidity and mortality in acute infectious diarrheal illnesses.
authors: Division of Gastroenterology, Nutrition and Hepatology, Department of Pediatrics, University of Florida, Gainesville, Florida;
authors: Lieqi
authors: L
authors: Tang
authors: Division of Gastroenterology, Nutrition and Hepatology, Department of Pediatrics, University of Florida, Gainesville, Florida;
authors: Minzhi
authors: M
authors: Peng
authors: Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong, People's Republic of China;
authors: Li
authors: L
authors: Liu
authors: Endocrine Research, VA Medical Center, University of California at San Francisco, San Francisco, California;
authors: Wenhan
authors: W
authors: Chang
authors: Department of Internal Medicine, Yale University, New Haven, Connecticut.
authors: Henry J
authors: HJ
authors: Binder
authors: Division of Gastroenterology, Nutrition and Hepatology, Department of Pediatrics, University of Florida, Gainesville, Florida; sam.cheng@ufl.edu.
authors: Sam X
authors: http://orcid.org/0000-0003-0252-9357
authors: SX
authors: Cheng
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002713:Chlorine / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D001639:Bicarbonates; D005227:Fatty Acids; D044169:Receptors, Calcium-Sensing; D002713:Chlorine; D000242:Cyclic AMP; D002118:Calcium
keywords: bicarbonate secretion; calcium-sensing receptor; diarrhea; short-chain fatty acid