Regulation of ductal bicarbonate transport by intracellular chloride and its role in pancreatic secretion

Abstract

[한글]

[영문]The exocrine pancreas creates strong alkaline fluid. However, how the human pancreatic duct cells secrete copious amount of bicarbonate (HCO3-) has long been a puzzle for more than a century since it was realized. The present study demonstrates that intracellular Cl- concentration ([Cl-]i)-sensitive mechanisms induces dynamic increase in the CFTR HCO3- permeability which play a pivotal role in the pancreatic HCO3- secretion. In the polarized PANC1 human pancreatic duct cells, CFTR activation rapidly decreased [Cl-]i in response to the luminal Cl- depletion. Interestingly, in human pancreatic tissues, CFTR-positive duct cells co-expressed WNK1, OSR1, and SPAK kinases, which are activated by low [Cl-]i. Notably, the WNK1-mediated OSR1 and SPAK activation by low [Cl-]i strongly increased CFTR HCO3- permeability in the CFTR-transfected HEK 293T, PANC1, and guinea pig pancreatic duct cells making CFTR primarily a HCO3- channel, which is essential for the secretion of pancreatic juice containing HCO3- at a concentration greater than 140 mM. In contrast, OSR1 and SPAK activation inhibited the CFTR-dependent Cl-/HCO3- exchange activity, which may reabsorb HCO3- from the high HCO3--containing pancreatic juice. These results indicate that the [Cl-]i-sensitive activation of WNK1-OSR1/SPAK pathway is the molecular switch to generate HCO3--rich fluids in the human pancreatic ducts.