Intracellular Ca<sup>2+</sup> Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives
Intracellular Ca<sup>2+</sup> 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&...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/11/4005 |
| Summary: | Intracellular Ca<sup>2+</sup> 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<sup>2+</sup> elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca<sup>2+</sup> is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca<sup>2+</sup> 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<sup>2+</sup> elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca<sup>2+</sup> stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca<sup>2+</sup> via the Orai1 Ca<sup>2+</sup> channel, a process known as store-operated Ca<sup>2+</sup> entry (SOCE). Intracellular Ca<sup>2+</sup> overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO<sub>3</sub><sup>-</sup> secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca<sup>2+</sup> 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<sup>2+</sup> overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca<sup>2+</sup> 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. |
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| ISSN: | 1661-6596 1422-0067 |