CFTR mediates cAMP- and Ca2+-activated duodenal epithelial HCO3- secretion

Abstract

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in duodenal alkaline secretion has not been directly examined. The aims of this series of experiments were to determine if CFTR mediates basal and stimulated duodenal epithelial HCO3- secretion. Utilizing the cystic fibrosis murine model (cftr(m1UNC)), we compared normal [CFTR(+/+)] littermates (34-46 days old) with CFTR(-/-) animals (34-39 days old). Anesthesia was induced and maintained with intraperitoneal Hypnorm-midazolam. The proximal duodenum (4-7 mm) was cannulated and perfused with 154 mM NaCl. Either forskolin (10(-6)-10(-4) M) or carbachol (10(-6)-10(-3) M) was perfused intraluminally to activate adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca2+-mediated HCO3- secretion, respectively. Effluent volumes were weighed and HCO3- quantitated by back titration. Basal HCO3- secretion was diminished significantly (P < 0.01) in CFTR(-/-)vs. normal CFTR(+/+) mice (2.8 +/- 0.5 vs. 5.3 +/- 0.4 micromol x cm(-1) x h(-1)). Moreover, in CFTR(-/-) mice, both forskolin- and carbachol-stimulated peak HCO3- secretions were fourfold less compared with those in CFTR(+/+) littermates (3.7 +/- 0.2 vs. 15.6 +/- 2.1 and 4.7 +/- 0.3 vs. 14.2 +/- 2.5 micromol x cm(-1) x h(-1), respectively; P < 0.01). In conclusion, CFTR plays a significant role in mediating basal, cAMP-, and Ca2+-activated duodenal epithelial HCO3- secretion.

Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease

“…Further, 115 mM luminal HCO 3 -greatly increased granule area in the Cftr-KO goblet cell, which was reminiscent of the early stages of CCH stimulation. Given the deficits of HCO 3 -secretion in the Cftr-KO intestine (50,64,65), losing local HCO 3 -stimulation may contribute to goblet cell enlargement with stored granules, which is often noted in histological sections of CF epithelia. Despite the positive effects of 115 mM HCO 3 -luminal superfusion, goblet cell dysfunction was still apparent in the Cftr-KO enteroids.…”

Secretagogues stimulate electrogenic HCO3–secretion in the ileum of the brushtail possum,Trichosurus vulpecula:evidence for the role of a Na+/HCO3– cotransporter

“…Early functional assays suggested that NBC, presumably pNBC, was present in the crypts of the rabbit (Knickelbein et al, 1988;Minhas and Field, 1994) and guinea pig (Macleod et al, 1996), but this has not been confirmed with direct measurements of the distribution of pNBC. Interestingly, in mouse (Praetorius et al, 2001) and rat duodenum, which are known to secrete HCO 3 - (Isenberg et al, 1993;Hogan et al, 1997), pNBC is expressed in the villous cells but not the crypt cells. Thus, at least in these rodents electrogenic HCO 3 -secretion driven by pNBC is primarily a function of the villous cells, as it is in the possum.…”

The distribution and expression of CFTR restricts electrogenic anion secretion to the ileum of the brushtail possum, Trichosurus vulpecula

“…In eutherian mammals, CFTR is intimately involved in intestinal secretion and deletion of CFTR in knockout mice results in the inhibition of both Cl -and HCO 3 -secretion (Hogan et al, 1997;Seidler et al, 1997). Therefore, we investigated whether the expression of the pCFTR in the different regions of the possum small intestine corresponded with the magnitude of the I sc response to secretagogues.…”

“…In addition, acid or secretagogues stimulate electrogenic HCO 3 -secretion, which is independent of Cl-HCO 3 exchanger activity (Seidler et al, 1997;Spiegel et al, 2003). This suggests the presence of an apical HCO 3 -conductance through which HCO 3 -exits the cells, most likely CFTR (Akiba et al, 2005;Hogan et al, 1997), because deletion of CFTR inhibits both intestinal Cl -and HCO 3 -secretion (Hogan et al, 1997;Seidler et al, 1997). Thus, CFTR has a central role in both electrogenic Cl -and HCO 3 -secretion in the eutherian intestinal tract.…”