Decreased calmodulin recruitment triggers PMCA4 dysfunction and pancreatic injury in cystic fibrosis

Abstract

Exocrine pancreatic damage is a common complication of cystic fibrosis (CF), which can significantly debilitate the quality of life and life expectancy of CF patients. The cystic fibrosis transmembrane conductance regulator (CFTR) has a major role in pancreatic ductal ion secretion, however, it presumably has an influence on intracellular signaling as well. Here we describe in multiple model systems, including iPSC-derived human pancreatic organoids from CF patients, that the activity of PMCA4 is impaired by the decreased expression of CFTR in ductal cells. The regulation of PMCA4, which colocalizes and physically interacts with CFTR on the apical membrane of the ductal cells, is dependent on the calmodulin binding ability of CFTR. Moreover, CFTR seems to be involved in the process of the apical recruitment of calmodulin, which enhances its role in calcium signaling and homeostasis. Sustained intracellular Ca2+ elevation in CFTR KO cells undermined the mitochondrial function and increased apoptosis. Based on these, the prevention of sustained intracellular Ca2+ overload may improve the exocrine pancreatic function and may have a potential therapeutic aspect in CF.

Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids

“…Fourth, to demonstrate the importance of ion flux in the lumen formation process we administered forskolin (10 µM) at distinct stages of organoid development, which induced lumen formation and swelling. As previously demonstrated, forskolin induces organoid-swelling by Cl-/Na+ influx due to cAMP-PKA pathway activation and CFTR phosphorylation 24,25 . When treating organoids from day 0 onwards, the organoids are forced to form large, mostly symmetric cysts (72%) or branched cysts (23%), whereas controls assume a thick branched morphology (Fig.…”