Abstract
Intracellular Ca(2+) 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(2+) elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca(2+) is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca(2+) 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(2+) elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca(2+) stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca(2+) via the Orai1 Ca(2+) channel, a process known as store-operated Ca(2+) entry (SOCE). Intracellular Ca(2+) overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO(3)(-) secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca(2+) 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(2+) overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca(2+) 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.