CFTR drives Na⁺- n HCO 3 − cotransport in pancreatic duct cells: a basis for defective HCO 3 − secretion in CF

Abstract

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.