The p.E152K-STIM1 mutation deregulates Ca²⁺ signaling contributing to chronic pancreatitis

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Intracellular calcium (Ca2+) deregulation can activate trypsin, a key factor in pancreatitis.
• Stromal interaction molecule-1 (STIM1) is crucial for maintaining Ca2+ balance in pancreatic acinar cells.

Purpose of the Study:

• To investigate the role of STIM1 variants in Ca2+ signaling and chronic pancreatitis susceptibility.
• To functionally characterize the STIM1 p.E152K variant and its impact on pancreatic cell function.

Main Methods:

• Analysis of 37 STIM1 variants from pancreatitis patient cohorts.
• Functional studies using patient-derived fibroblasts, HEK293T cells, and AR42J pancreatic cells.
• Assessment of Ca2+ release, store-operated Ca2+ entry (SOCE), trypsin activation, and cytotoxicity.

Main Results:

• The STIM1 p.E152K variant increased endoplasmic reticulum Ca2+ release and enhanced SOCE.
• This variant altered STIM1-SERCA interactions and SERCA pump activity.
• In pancreatic cells, p.E152K caused trypsin activation/secretion defects and increased cytotoxicity.

Conclusions:

• The STIM1 p.E152K variant dysregulates Ca2+ signaling in pancreatic acinar cells.
• This disruption provides a potential mechanism linking STIM1 variants to chronic pancreatitis.
• Altered Ca2+ handling by STIM1 variants may contribute to pancreatic acinar cell dysfunction and disease.