Fig. 6. A model of pancreatic duct fluid and HCO₃⁻ secretion.

Ductal fluid and HCO₃⁻ secretion is a two stage process. In the proximal duct IRBIT antagonizes the effect of the WNK/SPAK pathway to stimulate ductal secretion. HCO₃⁻ accumulates in the duct cytosol by NBCe1-B and exits into the lumen mostly by Slc26a6, which mediates 1Cl⁻/2HCO₃⁻ exchange, with CFTR recycling the Cl⁻. This result with osmotic secretion of HCO₃⁻ and together with transcellular Na⁺ fluxes through the paracellular pathway drives fluid secretion. The water is secreted by AQP1. The proximal duct thus absorbs part of the Cl⁻ and secretes as much as 100 mM HCO₃⁻ to secret large fraction of the fluid in the pancreatic juice. As the fluid arrives the more distal portions of the duct, the reduced luminal Cl⁻ and activated CFTR results in intracellular Cl⁻ concentration ([Cl⁻]_i) of less than 10 mM. The low [Cl⁻]_i activates WNK1 that phosphorylates SPAK/OSP1, which, in turn, acts on CFTR to change its Cl⁻/HCO₃⁻ selectivity, converting it primarily a HCO₃⁻ channel. At the same time the WNK/SPAK pathway inhibits the function of Slc26a6 to prevent HCO₃⁻ re-absorption. HCO₃⁻ efflux by CFTR thus determines the final HCO₃⁻ concentration in the secreted fluid.