RT Journal Article
SR Electronic
T1 Decreased calmodulin recruitment triggers PMCA4 dysfunction and pancreatic injury in cystic fibrosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.10.290940
DO 10.1101/2020.09.10.290940
A1 Tamara Madácsy
A1 Árpad Varga
A1 Noémi Papp
A1 Barnabás Deák
A1 Bálint Tél
A1 Petra Pallagi
A1 Viktória Szabó
A1 Júlia Fanczal
A1 Zoltan Rakonczay, Jr.
A1 Zsolt Rázga
A1 Meike Hohwieler
A1 Alexander Kleger
A1 Mike Gray
A1 Péter Hegyi
A1 József Maléth
YR 2020
UL http://biorxiv.org/content/early/2020/09/11/2020.09.10.290940.abstract
AB 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.