HCO3- secretion is a well-established physiologic process that is closely linked to overall fluid and electrolyte movement in 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 small and large intestine, regulates HCO3- secretion. Basal and induced HCO3- secretory responses to CaSR agonists were determined by pH stat techniques and short-circuit current measurements in mucosa from rat distal colon mounted in Ussing chambers. R568, a 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 CFTR-mediated HCO3- conductance, CaSR activation inhibits HCO3- secretion. Similarly, activation of CaSR by R568 stimulated Cl-- and SCFA- dependent 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.
- Calcium-sensing receptor
- bicarbonate secretion
- short-chain fatty acid
- short-circuit current
- Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology