Intracellular Ca2+ Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives.

Petra Pallagi,Árpád Varga,József Maléth,Tamara Madácsy

doi:10.3390/ijms21114005

Petra Pallagi, Árpád Varga + Show 2 more

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https://doi.org/10.3390/ijms21114005

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Intracellular Ca2+ 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 Ca2+ elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca2+ is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca2+ concentration is an early trigger for the development of acute pancreatitis (AP). Regardless of the aetiology, different forms of AP all exhibit sustained intracellular Ca2+ elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca2+ stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca2+ via the Orai1 Ca2+ channel, a process known as store-operated Ca2+ entry (SOCE). Intracellular Ca2+ overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO3- secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca2+ 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 Ca2+ overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca2+ 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.

Highlights

Acute pancreatitis (AP) is an inflammatory disease of the pancreas associated with significant morbidity and mortality
AP is primarily caused by impacted gallstones or heavy alcohol consumption; the incidence of iatrogenic AP caused by endoscopic retrograde cholangiopancreatography (ERCP) or drug administration has increased [5]
The toxic effects of bile acids on pancreatic acinar cells involve the activation of the G-protein-coupled cell surface bile acid receptor (Gpbar1) at the apical membrane, which contributes to the development of sustained Ca2+ elevation and its downstream effects [22]

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Introduction

Acute pancreatitis (AP) is an inflammatory disease of the pancreas associated with significant morbidity and mortality. Bile acids are known to trigger dose-dependent elevations in intracellular Ca2+ concentrations in isolated pancreatic acinar [18] and ductal cells [19] in vitro, which is due to Ca2+ release from intracellular stores via the activation of IP3 and ryanodine receptors, sarco-endoplasmic reticulum Ca2+ pump (SERCA) inhibition [20] and extracellular Ca2+ influx activation [21] (Figure 1). Bile acids inhibit intracellular ATP production and decreased ∆Ψm in acinar [23,24] and ductal cells [12].

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