TRPV6-mediated Store-operated Ca²⁺ Entry Participates in Pancreatic Acinar Cell Injury During Acute Pancreatitis

Suppressing toxic Ca²⁺ accumulation in pancreatic acinar cells (PACs) is the central therapeutic strategy of acute pancreatitis (AP). Store-operated Ca²⁺ entry (SOCE) represents an important mechanism promoting Ca²⁺ overload, which remains incompletely understood in AP. Transient receptor potential vanilloid 6 (TRPV6) is an ion channel highly selective to Ca²⁺, and its role in PACs or AP onset remains largely unknown.

We utilized human and mouse pancreata for TRPV6 expression using RNAscope and PACs for electrophysical currents and Ca²⁺ signals identification. Following RNA sequencing, we examined the interaction between TRPV6 and stromal interaction molecule 1 (STIM1) at the junctions between the endoplasmic reticulum (ER) membrane and the plasma membrane using coimmunoprecipitation, living cell imaging, and transmission electron microscopy. Finally, we established a mouse model using adeno virus-mediated pancreas conditional Trpv6 knockdown. We thereafter utilized a TRPV6 inhibitor to examine the effect of inhibiting TRPV6 on AP.

The in situ TRPV6 expression and cation currents were significantly enhanced in PACs during AP. Pancreatic genetic conditional knockdown and pharmacological blockade of TRPV6 both showed beneficial effect on AP mice, which may be attributed to the prevention of mitochondrial depolarization and trypsin activation in PACs. Additionally, TRPV6 was found to participate in ER store-deletion-induced Ca²⁺ signals in mouse and human PACs, and to interact with STIM1, implicating its involvement in mediating SOCE that contributes to AP pathology.

TRPV6 is a key player in Ca²⁺ overload in PACs and contributes to AP at least partly through mediating SOCE.