In:
American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 308, No. 10 ( 2015-05-15), p. G874-G883
Abstract:
Colonic bicarbonate (HCO 3 − ) 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 HCO 3 − secretion. Basal and induced HCO 3 − 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 HCO 3 − secretion but inhibited cyclic nucleotide-activated HCO 3 − secretion. Consequently, at physiological conditions (either at basal or during lumen acid challenge) when electroneutral Cl − /HCO 3 − and SCFA/HCO 3 − exchangers dominate, CaSR stimulates HCO 3 − secretion; in contrast, in experimental conditions that stimulate fluid and HCO 3 − secretion, e.g., when forskolin activates electrogenic cystic fibrosis transmembrane conductance regulator-mediated HCO 3 − conductance, CaSR activation inhibits HCO 3 − secretion. Corresponding changes in J HCO3 (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 HCO 3 − secretion and inhibited cAMP-dependent HCO 3 − 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 HCO 3 − 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 HCO 3 − secretion suggests that modulation of CaSR activity may provide a new therapeutic approach to correct HCO 3 − deficit and metabolic acidosis, a primary cause of morbidity and mortality in acute infectious diarrheal illnesses.
Type of Medium:
Online Resource
ISSN:
0193-1857
,
1522-1547
DOI:
10.1152/ajpgi.00341.2014
Language:
English
Publisher:
American Physiological Society
Publication Date:
2015
detail.hit.zdb_id:
1477329-6
SSG:
12
Permalink
