Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC193
Role of basolateral Cl--HCO3- exchange in HCO3- secretion in a computational model of electrolyte transport by pancreatic duct epithelium
M. Yamaguchi1, M. Steward2, A. Yamamoto1, Y. Sohma3, S. Ko4, T. Kondo1, H. Ishiguro1
1. Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan. 2. Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. 3. Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan. 4. Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Pancreatic duct epithelium produces a HCO3--rich (~140 mM) isotonic fluid secretion, which conveys the protein-rich acinar secretion to the duodenum. It is generally thought that Na+-HCO3- cotransport (NBC1) provides a major route for HCO3- accumulation across the basolateral membrane. However, the role of the electroneutral Cl--HCO3- exchange (AE2) at the basolateral membrane is not well understood. To investigate the role of AE2, we have constructed two simulation models of the pancreatic duct epithelial cell using MATLAB/Simulink: a luminal-perfusion model and a fluid-secreting model. In these models, NBC1, Na+-H+ exchange (NHE1), AE2, Na+/K+-ATPase, and a K+ conductance are present at the basolateral membrane, and HCO3- and Cl- conductances mediated by CFTR (cystic fibrosis transmembrane conductance regulator) and 1Cl--2HCO3- exchange (SLC26A6) are present at the apical membrane. In the fluid-secreting model, the luminal electrolyte composition was determined by the secreted fluid secretion and the same amount of fluid was excreted from the lumen. At the steady state, HCO3- concentration of the secreted fluid equals luminal HCO3- concentration ([HCO3-]L). Previous studies have suggested that NHE1 is activated by acidic intracellular pH (pHc). In our kinetic model of NHE1 we have therefore added allosteric modulation by H+ with a Hill coefficient of 3 and a pKa of 6.7. It has been predicted that AE2 would tend to dissipate the accumulation of intracellular HCO3-, resulting in a reduced driving force for apical HCO3- secretion. Indeed, our measurements of intracellular [Cl-] in guinea-pig pancreatic duct (Ishiguro et al, 2002) suggest that the activity of AE2 may be suppressed following cAMP stimulation. In the present study we examined the effects of AE2 inhibition on HCO3- secretion in the fluid-secreting model. When AE2 was at its basal level, the secreted [HCO3-]L was predicted to be ~85 mM. When AE2 activity was reduced to 50%, 10%, or 5%, [HCO3-]L increased to ~102 mM, ~132 mM, and ~140 mM respectively (pHc was 7.30, 7.35, and 7.36 and apical membrane potential was -55 mV, -59 mV, and -60 mV). In the latter case, the rate of steady-state fluid secretion was ~1.2 nl min-1 mm-2 (per unit area of apical membrane), which is consistent with experimental data from guinea-pig pancreatic duct (Ishiguro et al, 1998). These results suggest that inhibition of AE2 is a prerequisite for HCO3--rich fluid secretion by pancreatic duct.
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