Brake adjustment: Ca²⁺ entry pathway provides a novel target for acute pancreatitis therapy

Acute pancreatitis (AP) is accompanied by intense abdominal pain that often requires hospital admission, but no therapies directed at causes of the disease yet exist (1). Evidence accumulated over decades of research revealed that the initial events of AP target the pancreatic acinar cell, where digestive enzymes are produced (1). Especially during the past 25 years, a hypothesis that has gained wide acceptance is that an excess of acinar cell cytosolic Ca²⁺ (Ca²⁺_cyt) is a key initial trigger of AP pathology (1-3). This Ca²⁺_cyt overload likely contributes to premature trypsin activation, a hallmark of AP pathology, as well as a plethora of other responses (4,5). Depending on its extent and persistence, Ca²⁺_cyt overload in the acinar cell may perturb cellular energetics, confound complex secretory functions and homeostatic processes like autophagy, or induce cell death.