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Ca²⁺-activated Cl^- channels can substitute for CFTR in stimulation of pancreatic duct bicarbonate secretion ¹

ÁKOS ZSEMBERY^*,,, MARIO STRAZZABOSCO and JÜRG GRAF^*2

^* Department of General and Experimental Pathology, University of Vienna, Vienna, Austria;
Istituto di Medicina Interna, Università ed Azienda Ospedaliera di Padova, Padua, Italy; and
Department of Pathophysiology, Semmelweis University, Faculty of Medicine, Budapest, Hungary

²Correspondence: Department of General and Experimental Pathology, University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria. E-mail: juerg.graf{at}univie.ac.at

This study addresses the mechanisms by which a defect in CFTR impairs pancreatic duct bicarbonate secretion in cystic fibrosis. We used control (PANC-1) and CFTR-deficient (CFPAC-1; F508 mutation) cell lines and measured HCO₃^- extrusion by the rate of recovery of intracellular pH after an alkaline load and recorded whole cell membrane currents using patch clamp techniques. 1) In PANC-1 cells, cAMP causes parallel activation of Cl^- channels and of HCO₃^- extrusion by DIDS-sensitive and Na⁺-independent Cl^-/HCO₃^- exchange, both effects being inhibited by Cl^- channel blockers NPPB and glibenclamide. 2) In CFPAC-1 cells, cAMP fails to stimulate Cl^-/HCO₃^- exchange and Cl^- channels, except after promoting surface expression of F508-CFTR by glycerol treatment. Instead, raising intracellular Ca²⁺ concentration to 1 µmol/l or stimulating purinergic receptors with ATP (10 and 100 µmol/l) leads to parallel activation of Cl^- channels and HCO₃^- extrusion. 3) K⁺ channel function is required for coupling cAMP- and Ca²⁺-dependent Cl^- channel activation to effective stimulation of Cl^-/HCO₃^- exchange in control and CF cells, respectively. It is concluded that stimulation of pancreatic duct bicarbonate secretion via Cl^-/HCO₃^- exchange is directly correlated to activation of apical membrane Cl^- channels. Reduced bicarbonate secretion in cystic fibrosis results from defective cAMP-activated Cl^- channels. This defect is partially compensated for by an increased sensitivity of CF cells to purinergic stimulation and by alternative activation of Ca²⁺-dependent Cl^- channels, mechanisms of interest with respect to possible treatment of cystic fibrosis and of related chronic pancreatic diseases.—Zsembery, Á., Strazzabosco, M., Graf, J. Ca²⁺-activated Cl^- channels can substitute for CFTR in stimulation of pancreatic duct bicarbonate secretion.

Key Words: cystic fibrosis • anion exchange • purinergic stimulation • K⁺ channel function

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