Mechanisms of Bicarbonate Secretion in the Pancreatic Duct

Abstract

In many species the pancreatic duct epithelium secretes HCO3- ions at a concentration of around 140 mM by a mechanism that is only partially understood. We know that HCO3- uptake at the basolateral membrane is achieved by Na+-HCO3- cotransport and also by a H+-ATPase and Na+/H+ exchanger operating together with carbonic anhydrase. At the apical membrane, the secretion of moderate concentrations of HCO3- can be explained by the parallel activity of a Cl-/HCO3- exchanger and a Cl- conductance, either the cystic fibrosis transmembrane conductance regulator (CFTR) or a Ca2+-activated Cl- channel (CaCC). However, the sustained secretion of HCO3- into a HCO- -rich luminal fluid cannot be explained by conventional Cl-/HCO3- exchange. HCO3- efflux across the apical membrane is an electrogenic process that is facilitated by the depletion of intracellular Cl-, but it remains to be seen whether it is mediated predominantly by CFTR or by an electrogenic SLC26 anion exchanger.

Functional coupling of apical Cl−/HCO3− exchange with CFTR in stimulated HCO3− secretion by guinea pig interlobular pancreatic duct

“…In the presence of high luminal [Cl Ϫ ], apical Cl Ϫ /HCO 3 Ϫ exchange has been proposed to mediate most HCO 3 Ϫ secretion, with CFTR HCO 3 Ϫ conductance playing a minor role (1,37). In this setting CFTR is thought to support luminal Cl Ϫ -dependent Ϫ secretion by recycling intracellular Cl Ϫ across the apical membrane (30,45).…”

SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization

“…This alkaline fluid prevents premature intraductal activation of the digestive proenzymes secreted by pancreatic acinar cells and delivers them safely to the intestinal lumen, where the activated enzymes facilitate nutrient absorption by enterocytes (34,49). Secretin stimulates HCO 3 Ϫ secretion through activation of adenylate cyclase, with subsequent activation of HCO 3 Ϫ transport across the ductal epithelium apical membrane via the cystic fibrosis transmembrane regulator (CFTR) Cl Ϫ channel and Slc26 Cl Ϫ /HCO 3 Ϫ exchanger(s) (20,48).…”

“…However, the axial expression pattern of Slc26a3 and Slc26a6 along the pancreatic duct remains unknown. Moreover, mathematical modeling predicts a modest increase in ductal HCO 3 Ϫ secretion resulting from the presence of lumenal electrogenic anion exchange (49). In addition, numerous experiments have not detected electrogenicity of Cl Ϫ /HCO 3 Ϫ exchange mediated by Slc26a6 and Slc26a3 (1,9,17,26,29,31,59).…”

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

“…A similar model to explain HCO 3 -secretion by the pancreatic duct of non-rodent eutherian mammals has been proposed (Park et al, 2010;Steward et al, 2005). CFTR from eutherian mammals also has a relatively low P HCO3 (Gray et al, 1993;Gray et al, 1990;Linsdell et al, 1997;O'Reilly et al, 2000;Poulsen et al, 1994).…”

“…The Na + ,K + -ATPase provides the driving force for the Na + -dependent accumulation of HCO 3 -across the basolateral membrane, which is evident from the inhibitory affect of ouabain on the ileal secretory response (Bartolo et al, 2009a). Although pNBCe1 is likely to be electrogenic (Pushkin and Kurtz, 2006;Romero et al, 2004), the basolateral K + channels are necessary to maintain both charge and mass balance and the driving force for HCO 3 -exit across the apical membrane (Steward et al, 2005).…”