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. 2015 May 15;308(10):G874-83.
doi: 10.1152/ajpgi.00341.2014. Epub 2015 Mar 19.

Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon

Lieqi Tang  1 , Minzhi Peng  1 , Li Liu  2 , Wenhan Chang  3 , Henry J Binder  4 , Sam X Cheng  5
Affiliations

Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon

Lieqi Tang et al. Am J Physiol Gastrointest Liver Physiol. .

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.

Keywords: bicarbonate secretion; calcium-sensing receptor; diarrhea; short-chain fatty acid.

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Figures

Fig. 1.
Fig. 1.
Effects of extracellular Ca2+ and calcium-sensing receptor (CaSR) agonist R568 on basal HCO3− secretion. A and B: representatives of 3 recordings of luminal pH responses of colonic mucosa to absence and presence of a serosa-to-lumen-directed HCO3− gradient and carbachol (CCH, 100 μM, serosa) (A) and normal vs. low [Ca2+]o (B). The presence or absence of HCO3− in the lumen or serosa is shown as indicated. C: serosal to mucosal JHCO3 peak responses to R568 (10 μM, serosa). The basal tissue resistance (Ω/cm2) and Isc (μeq·h−1·cm−2) were 69 ± 7 and 1.44 ± 0.32 at 0.5 mM [Ca2+]o vs. 72 ± 6 and 1.10 ± 0.10 at 1.2 mM [Ca2+]o (P > 0.05). Data are means ± SE of 5 experiments. *P < 0.05 vs. control (with no R568).
Fig. 2.
Fig. 2.
Effect of CaSR agonist R568 on acid-induced HCO3− secretion. A: representatives of pH recovery responses in the presence vs. absence of R568 (10 μM, serosa). The addition of R568 is shown as indicated. B: summary of ΔpH recovery rates (stimulated peak values above basal levels before additions of R568 or vehicle). Basal levels of acid-induced pH recovery were 0.015 ± 0.001 pH U·min−1·cm−2. The tissue resistance (Ω/cm2) and Isc (μeq·h−1·cm−2) at the end of 60-min experiments were 50 ± 12 and 1.74 ± 0.20 without challenge and 46 ± 10 and 1.97 ± 0.23 with acid challenges (P > 0.05). Data are means ± SE of 5 experiments. *P < 0.05 vs. control (with no R568).
Fig. 3.
Fig. 3.
Effect of CaSR agonist R568 on secretagogue-induced HCO3− secretion and HCO3− current. Shown are JHCO3 (A) and Isc (C) responses to forskolin (FSK, 500 nM, serosa) ± R568 (10 μM, serosa), assayed in lumen Cl−-containing Ringer solution. The changes induced by FSK in the absence vs. presence of R568 are summarized in B (ΔJHCO3FSK) and D (ΔISCFSK). The basal tissue resistance and Isc under these conditions were as follows: 68 ± 4 Ω/cm2 and 1.51 ± 0.22 μeq·h−1·cm−2. Data are means ± SE of 8 experiments. **P < 0.01 vs. control (with no R568); ##P < 0.01 vs. FSK.
Fig. 4.
Fig. 4.
Activation of CaSR stimulates Cl−-dependent HCO3− secretion. A: JHCO3 responses to the presence vs. absence of lumen Cl−. B: ΔJHCO3Cl (i.e., Cl−-dependent HCO3− secretion) responses to the presence vs. absence of R568 (10 μM, serosa). The basal tissue resistance (Ω/cm2) and Isc (μeq·h−1·cm−2) were 68 ± 11 and 1.44 ± 0.32 in the presence vs. 95 ± 15 and 1.01 ± 0.08 in the absence of lumen Cl− (P > 0.05). Data are means ± SE of 3–5 experiments. *P < 0.05 and **P < 0.01 vs. control (1st bar).
Fig. 5.
Fig. 5.
Activation of CaSR stimulates SCFA-dependent HCO3− secretion. Two equally longitudinally divided pieces of mucosa from same colon were mounted into 2 Ussing chambers. 1 piece was treated first in the presence then absence of lumen short-chain fatty acid (SCFA), whereas the other piece was treated first in the presence then absence of serosa HCO3−. Shown are representative recordings (A and B) and quantitative summary (C) of these JHCO3 responses. The ΔJHCO3SCFA (i.e., SCFA-dependent HCO3− secretion) was calculated, and its responses to the presence vs. absence of R568 (10 μM, serosa) are shown in D. The basal tissue resistance (Ω/cm2) and Isc (μeq·h−1·cm−2) were 126 ± 26 and 0.71 ± 0.17 in the presence vs. 95 ± 5 and 1.01 ± 0.08 in the absence of lumen 25 mM isobutyrate (P > 0.05). Data are means ± SE of 3–5 experiments. *P < 0.05 and **P < 0.01 vs. control (1st bar).
Fig. 6.
Fig. 6.
Activation of CaSR inhibits cAMP-dependent HCO3− secretion and HCO3− current. Shown are JHCO3 (A) and Isc (C) responses to FSK (500 nM, serosa) ± R568 (10 μM, serosa), assayed in lumen Cl−-free Ringer solution. The changes induced by FSK in the absence vs. presence of R568 are summarized in B (ΔJHCO3FSK) and D (ΔISCFSK). The basal tissue resistance and Isc under these conditions were 103 ± 3 Ω/cm2 and 0.87 ± 0.05 μeq·h−1·cm−2. Data are means ± SE of 4–7 experiments. **P < 0.01 vs. control (1st bar); ##P < 0.01 vs. FSK alone (2nd bar).
Fig. 7.
Fig. 7.
R568 fails to stimulate Cl−- and SCFA- dependent and inhibit cAMP-dependent HCO3− secretion in colons of CaSR-null mice. Colonic mucosa from wild-type (CaSR+/+) (A–C) and knockout (CaSR−/−) mice (D–F) were isolated and treated, and activities of the 3 HCO3− transporters were assayed as in rats. Data are means ± SE of 4–6 experiments. *P < 0.05 vs. control (1st bar).
Fig. 8.
Fig. 8.
Cellular model of CaSR regulation of HCO3− secretion in colonocytes of rat distal colon. Top: R568 acting via CaSR causes enhancement of HCO3− secretion in surface epithelial cells by stimulation of luminal Cl−-dependent HCO3− secretion via apical Cl−/HCO3− exchange and stimulation of luminal SCFA-dependent HCO3− secretion mediated by apical SCFA/HCO3− exchange. Bottom: CaSR reduces HCO3− secretion in the crypt epithelial cells through inhibition of a cAMP-dependent HCO3− secretory process that may involve a 5-nitro-2-(3-phenylpropylamino)benzoic acid/glibenclamide-sensitive apical anion channel such as cystic fibrosis transmembrane conductance regulator (CFTR) and/or a basolateral HCO3− entry mechanism(s). +, stimulation; -, inhibition.
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