Ca2+‐activated Cl− channels can substitute for CFTR in stimulation of pancreatic duct bicarbonate secretion
Open Access
- 1 November 2000
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 14 (14) , 2345-2356
- https://doi.org/10.1096/fj.99-0509com
Abstract
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; ΔF508 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 ΔF508-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, A., Strazzabosco, M., Graf, J. Ca2+-activated Cl− channels can substitute for CFTR in stimulation of pancreatic duct bicarbonate secretion. FASEB J. 14, 2345–2356 (2000)Keywords
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