Deletion of TRPC3 in Mice Reduces Store-Operated Ca²⁺ Influx and the Severity of Acute Pancreatitis

Background & Aims: Receptor-stimulated Ca²⁺ influx is a critical component of the Ca²⁺ signal and mediates all cellular functions regulated by Ca²⁺. However, excessive Ca²⁺ influx is highly toxic, resulting in cell death, which is the nodal point in all forms of pancreatitis. Ca²⁺ influx is mediated by store-operated channels (SOCs). The identity and function of the native SOCs in most cells is unknown. Methods: Here, we determined the role of deletion of Trpc3 in mice on Ca²⁺ signaling, exocytosis, intracellular trypsin activation, and pancreatitis. Results: Deletion of TRPC3 reduced the receptor-stimulated and SOC-mediated Ca²⁺ influx by about 50%, indicating that TRPC3 functions as an SOC in vivo. The reduced Ca²⁺ influx in TRPC3^-/- acini resulted in reduced frequency of the physiologic Ca²⁺ oscillations and of the pathologic sustained increase in cytosolic Ca²⁺ levels caused by supramaximal stimulation and by the toxins bile acids and palmitoleic acid ethyl ester. Consequently, deletion of TRPC3 shifted the dose response for receptor-stimulated exocytosis and prevented the pathologic inhibition of digestive enzyme secretion at supramaximal agonist concentrations. Accordingly, deletion of TRPC3 markedly reduced intracellular trypsin activation and excessive actin depolymerization in vitro and the severity of pancreatitis in vivo. Conclusions: These findings establish the native TRPC3 as an SOC in vivo and a role for TRPC3-mediated Ca²⁺ influx in the pathogenesis of acute pancreatitis and suggest that TRPC3 should be considered a target for prevention of pancreatic damage in acute pancreatitis.