Apical Cl-/HCO3- exchanger stoichiometry in the modeling of HCO3- transport by pancreatic duct epithelium

Pancreatic duct cells secrete a HCO3--rich (～140 mM) fluid. Using a computer model of the pancreatic duct, Sohma, et al. have demonstrated that the activity of a Cl-/ HCO3- exchanger with a 1 : 1 stoichiometry at the apical membrane would have to be suppressed in order to achieve such a HCO3--rich secretion. Recently the apical exchanger in pancreatic ducts has been identified as SLC26A6 and this probably mediates most of Cl--dependent HCO3- secretion across the apical membrane. SLC26A6 is reported to mediate electrogenic Cl-/2HCO3- exchange when expressed in Xenopus oocytes. To assess the implications of this 1 : 2 stoichiometry for HCO3- secretion, we have reconstructed the Sohma model using MATLAB/Simulink. To do this we have formulated an expression for the turnover rate of Cl-/2HCO3- exchange using network thermodynamics and we have estimated the constants from published experimental data. Preliminary data suggest that the 1 : 2 stoichiometry of SLC26A6 would favor HCO3- secretion at higher concentrations

Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium

KEY POINTS: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO(3) (−) concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea‐pig pancreatic ducts. The model was readily able to secrete 140 mm HCO(3) (−). Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO(3) (−) concentrations is to minimize the secretion of Cl(−) ions. These findings help to clarify the mechanism responsible for pancreatic HCO(3) (−) secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. ABSTRACT: A computational model of guinea‐pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO(3) (−) ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least‐squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP‐stimulated secretion were well replicated by increasing the activities of the basolateral Na(+)‐HCO(3) (−) cotransporter (NBC1) and apical Cl(−)/HCO(3) (−) exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K(+) permeability and apical Cl(−) and HCO(3) (−) permeabilities (CFTR), and reducing the activity of the basolateral Cl(−)/HCO(3) (−) exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO(3) (−) at a rate of ∼3 nl min(−1) mm(−2), which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl(−)/HCO(3) (−) exchange via SLC26A6 at the apical membrane were able to support a HCO(3) (−)‐rich secretion. Raising the HCO(3) (−)/Cl(−) permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO(3) (−) concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl(−) concentration following cAMP stimulation and thereby maximizing the secreted HCO(3) (−) concentration. The addition of a basolateral Na(+)‐K(+)‐2Cl(−) cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl(−) and resulted in a lower secreted HCO(3) (−) concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl(−) secretion is the main requirement for secreting 140 mm HCO(3) (−)