earticle

영어

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. Present study firstly reports a novel mechanism whereby intracellular Cl- concentration ([Cl-]i)-sensitive kinases play a critical role in pancreatic HCO3- secretion. Recently, two related kinase families, with-no-lysine (WNK) kinases and sterile 20 (STE20)-like kinases, have emerged as osmotic sensors that modulate diverse ion transporters. In general, WNK kinases, including WNK1, are activated by osmotic stress such as a decrease in [Cl-]i, and subsequently phosphorylate and activate downstream STE20-like kinases, especially OSR1 and SPAK. In human pancreatic tissues, CFTR-positive duct cells co-expressed WNK1, OSR1, and SPAK kinases. Interestingly, CFTR activation greatly reduced [Cl-]i, and this in turn induced the activation of WNK1-OSR1/SPAK kinase cascade. Notably, the WNK1-mediated OSR1 and SPAK activation by low [Cl-]i strongly increased CFTR HCO3- permeability making CFTR primarily a HCO3- channel, which is essential for the secretion of pancreatic juice containing 140 mM HCO3-. 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 findingssuggest that the dynamic regulation of CFTR and anion exchange activity, via the [Cl-]i-sensitive WNK1-OSR1/SPAK pathway, is the molecular switch that generates a HCO3--rich fluid in the human pancreatic duct.