Alcoholic pancreatitis and
hepatitis are frequent, potentially lethal diseases with limited treatment options. Our previous study reported that the expression of CFTR Cl- channel is impaired by
ethanol in pancreatic ductal cells leading to more severe alcohol-induced
pancreatitis. In addition to determining epithelial ion secretion, CFTR has multiple interactions with other
proteins, which may influence intracellular Ca2+ signaling. Thus, we aimed to investigate the impact of
ethanol-mediated CFTR damage on intracellular Ca2+ homeostasis in pancreatic ductal epithelial cells and cholangiocytes. Human and mouse pancreas and liver samples and organoids were used to study ion secretion, intracellular signaling,
protein expression and interaction. The effect of PMCA4 inhibition was analyzed in a mouse model of alcohol-induced
pancreatitis. The decreased CFTR expression impaired PMCA function and resulted in sustained intracellular Ca2+ elevation in
ethanol-treated and mouse and human pancreatic organoids. Liver samples derived from
alcoholic hepatitis patients and
ethanol-treated mouse liver organoids showed decreased CFTR expression and function, and impaired PMCA4 activity. PMCA4 co-localizes and physically interacts with CFTR on the apical membrane of polarized epithelial cells, where CFTR-dependent
calmodulin recruitment determines PMCA4 activity. The sustained intracellular Ca2+ elevation in the absence of CFTR inhibited mitochondrial function and was accompanied with increased apoptosis in pancreatic epithelial cells and PMCA4 inhibition increased the severity of alcohol-induced AP in mice. Our results suggest that improving Ca2+ extrusion in epithelial cells may be a potential novel therapeutic approach to protect the exocrine pancreatic function in
alcoholic pancreatitis and prevent the development of
cholestasis in
alcoholic hepatitis.