Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon.
نویسندگان
چکیده
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.
منابع مشابه
Calcium - Sensing Receptor Stimulates Cl - - and SCFA - dependent but Inhibits cAMP - 1 dependent HCO 3 - Secretion in Colon
Division of Gastroenterology, Nutrition and Hepatology, Department of Pediatrics, 4 University of Florida, Gainesville, FL, USA 5 Department of Pediatrics, Guangzhou Women and Children’s medical Center, 6 Guangzhou, Guangdong, PRC 7 Endocrine Research, VA Medical Center, University of California at San Francisco, San 8 Francisco, CA, USA 9 Department of Internal Medicine, Yale University, New H...
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ورودعنوان ژورنال:
- American journal of physiology. Gastrointestinal and liver physiology
دوره 308 10 شماره
صفحات -
تاریخ انتشار 2015