CFTR Functions as a Bicarbonate Channel in Pancreatic Duct Cells

Abstract

Pancreatic duct epithelium secretes a HCO₃⁻-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO₃⁻ permeability of CFTR provides a pathway for apical HCO₃⁻ efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO₃⁻ induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pH_i) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K⁺ concentration. Apical HCO₃⁻ fluxes activated by cyclic AMP were independent of Cl⁻ and luminal Na⁺, and substantially inhibited by the CFTR blocker, CFTR_inh-172. Furthermore, comparable HCO₃⁻ fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (ΔF) mice. To estimate the HCO₃⁻ permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO₃⁻ and 24 mM Cl⁻ in the presence of 5% CO₂. From the changes in pH_i, membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO₃⁻ across the apical membrane were determined and used to calculate the HCO₃⁻ permeability. Our estimate of ∼0.1 µm sec⁻¹ for the apical HCO₃⁻ permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO₃⁻ secretion. This suggests that CFTR functions as a HCO₃⁻ channel in pancreatic duct cells, and that it provides a significant pathway for HCO₃⁻ transport across the apical membrane.