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American Journal of Physiology-Gastrointestinal and Liver Physiology

Year: 2009  |  Volume: 296  |  Issue: 6  |  Page No.: 1307 - 1317

Functional coupling of apical Cl-/HCO3- exchange with CFTR in stimulated HCO3- secretion by guinea pig interlobular pancreatic duct

A. K Stewart, A Yamamoto, M Nakakuki, T Kondo, S. L Alper and H. Ishiguro

Abstract

Pancreatic ductal epithelium produces a HCO3-rich fluid. HCO3 transport across ductal apical membranes has been proposed to be mediated by both SLC26-mediated Cl/HCO3 exchange and CFTR-mediated HCO3 conductance, with proportional contributions determined in part by axial changes in gene expression and luminal anion composition. In this study we investigated the characteristics of apical Cl/HCO3 exchange and its functional interaction with Cftr activity in isolated interlobular ducts of guinea pig pancreas. BCECF-loaded epithelial cells of luminally microperfused ducts were alkalinized by acetate prepulse or by luminal Cl removal in the presence of HCO3-CO2. Intracellular pH recovery upon luminal Cl restoration (nominal Cl/HCO3 exchange) in cAMP-stimulated ducts was largely inhibited by luminal dihydro-DIDS (H2DIDS), accelerated by luminal CFTR inhibitor inh-172 (CFTRinh-172), and was insensitive to elevated bath K+ concentration. Luminal introduction of CFTRinh-172 into sealed duct lumens containing BCECF-dextran in HCO3-free, Cl-rich solution enhanced cAMP-stimulated HCO3 secretion, as calculated from changes in luminal pH and volume. Luminal Cl removal produced, after a transient small depolarization, sustained cell hyperpolarization of ~15 mV consistent with electrogenic Cl/HCO3 exchange. The hyperpolarization was inhibited by H2DIDS and potentiated by CFTRinh-172. Interlobular ducts expressed mRNAs encoding CFTR, Slc26a6, and Slc26a3, as detected by RT-PCR. Thus Cl-dependent apical HCO3 secretion in pancreatic duct is mediated predominantly by an Slc26a6-like Cl/HCO3 exchanger and is accelerated by inhibition of CFTR. This study demonstrates functional coupling between Cftr and Slc26a6-like Cl/HCO3 exchange activity in apical membrane of guinea pig pancreatic interlobular duct.

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