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HORMONES AND SIGNALING

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

¹Renal Division and Molecular and Vascular Medicine Unit, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts; and ²Human Nutrition, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan

Submitted 14 December 2008 ; accepted in final form 27 March 2009

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.

bicarbonate; Slc26; cystic fibrosis transmembrane conductance regulator; forskolin; H₂DIDS