Intracellular Ca Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives.

Intracellular Ca signalling is a major signal transductional pathway in non-excitable cells, responsible for the regulation of a variety of physiological functions. In the secretory epithelial cells of the exocrine pancreas, such as acinar and ductal cells, intracellular Ca elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca concentration is an early trigger for the development of acute pancreatitis (AP). Regardless of the aetiology, different forms of AP all exhibit sustained intracellular Ca elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca via the Orai1 Ca channel, a process known as store-operated Ca entry (SOCE). Intracellular Ca overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca elevation further contributes to cell dysfunction, leading to mitochondrial damage and cell death. Translational studies of AP identified several potential target molecules that can be modified to prevent intracellular Ca overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca influx and protect cells from injury, is currently being tested in clinical trials. In this review, we will summarise the recent advances in the field, with a special focus on the translational aspects of the basic findings.