| First Author | Tang L | Year | 2015 |
| Journal | Am J Physiol Gastrointest Liver Physiol | Volume | 308 |
| Issue | 10 | Pages | G874-83 |
| PubMed ID | 25792563 | Mgi Jnum | J:224227 |
| Mgi Id | MGI:5661757 | Doi | 10.1152/ajpgi.00341.2014 |
| Citation | Tang L, et al. (2015) Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon. Am J Physiol Gastrointest Liver Physiol 308(10):G874-83 |
| abstractText | 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 (mueq.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. |
