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.