CFTR drives Na+-nHCO-3 cotransport in pancreatic duct cells: a basis for defective HCO-3 secretion in CF.
Pancreatic dysfunction in patients with cystic fibrosis (CF) is felt to result primarily from impairment of ductal HCO-3 secretion. We provide molecular evidence for the expression of NBC-1, an electrogenic Na+-HCO-3 cotransporter (NBC) in cultured human pancreatic duct cells exhibiting physiological features prototypical of CF duct fragments (CFPAC-1 cells) or normal duct fragments [CAPAN-1 cells and CFPAC-1 cells transfected with wild-type CF transmembrane conductance regulator (CFTR)]. We further demonstrate that 1) HCO-3 uptake across the basolateral membranes of pancreatic duct cells is mediated via NBC and 2) cAMP potentiates NBC activity through activation of CFTR-mediated Cl- secretion. We propose that the defect in agonist-stimulated ductal HCO-3 secretion in patients with CF is predominantly due to decreased NBC-driven HCO-3 entry at the basolateral membrane, secondary to the lack of sufficient electrogenic driving force in the absence of functional CFTR.
Shumaker
H
H
Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0585, USA.
Amlal
H
H
Frizzell
R
R
Ulrich
C D
CD
Soleimani
M
M
D000595:Amino Acid Sequence; D001639:Bicarbonates / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D004357:Drug Synergism; D004553:Electric Conductivity; D004594:Electrophysiology; D006801:Humans; D008969:Molecular Sequence Data; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027982:Sodium-Bicarbonate Symporters; D014018:Tissue Distribution
D001639:Bicarbonates; C505032:CFTR protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D027982:Sodium-Bicarbonate Symporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP