ATP regulates Cl− and K+ channels in human pancreatic ducts

Abstract

Pancreas is one of the major organs affected by cystic fibrosis. Purinergic receptors may provide novel strategies for up‐regulation of pancreatic secretion. Our aim was to elucidate how purineric receptors regulate ion transport in human pancreatic ducts and identify Cl− and K+ channels. Transepithelial transport was monitored in monolayers of Capan‐1 and CFPAC‐1 cells in Ussing chambers. Apical ATP/UTP stimulated CFTR and Ca2+‐activated Cl−channels, which were inhibited by CFTRinh‐172 and niflumic acid, respectively. Basolateral ATP stimulated CFTR. In CFPAC‐1 cells (with mutated CFTR), basolateral ATP/UTP had negligible effects. In Capan‐1 cells, effects of DC‐EBIO and clotrimazole indicated functional expression of the intermediate conductance K+ channels (IK, KCa3.1). Apical effects of ATP/UTP were greatly potentiated by IK opener DC‐EBIO. On mRNA and protein level we showed that Capan‐1 cells expressed TMEM16A/ANO1 and KCa3.1. We conclude that in human pancreatic duct cells, ATP/UTP regulates via P2 receptors both Cl− channels (ANO1 and CFTR) and K+ channels (KCa3.1). The K+ channels provide the driving force for Cl− channel‐dependent secretion, and luminal ATP provided locally or from acini potentiate secretory processes.Funded: the Lundbeck Foundation;The Danish Council for Independent Research | Natural Sciences