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Abstract

150 mM HCO3 - How Does the Pancreas Do It? Clues from Computer Modelling of the Duct Cell

Cystic fibrosis (CF) takes its name from the pathological changes that occur in the pancreas. Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed in the pancreatic ductal epithelium and plays a key role in ductal HCO3 - secretion. In humans, the pancreatic duct secretes near isotonic NaHCO3. Experimental data suggests that HCO3 - secretion occurs via apical Cl- /HCO3 - exchangers working in parallel with Clchannels (CFTR and calcium activated chloride channels, CaCC). Programming the currently available experimental data into our computer model [1, 2] (based on network thermodynamics) shows that while the anion exchanger/Cl- channel mechanism will produce a relatively large volume of a HCO3 - -rich fluid, it can only raise the luminal HCO3 - concentration up to about 70 mM. To achieve secretion of about 150 mM NaHCO3 it is necessary to modulate the properties of the apical membrane transporters as the secreted fluid flows down the ductal system. On the basis of our computer simulations, we propose that HCO3 - secretion occurs mainly via the exchanger in duct segments near the acini (luminal HCO3 - concentration up to about 70 mM), but mainly via channels further down the ductal tree (raising luminal HCO3 - to about 150 mM). We speculate that the switch between these two secretory mechanisms is controlled by a series of luminal signals (e.g. pH, HCO3 - concentration) acting on the apical membrane transporters in the duct cell.


Author(s):

Yoshiro Sohma, Michael A Gray, Yusuke Imai, Barry E Argent



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