Blocking TRPM4 alleviates pancreatic acinar cell damage via an NMDA receptor-dependent pathway in acute pancreatitis.

Abstract

Background: Mitochondrial dysfunction caused by Ca²⁺ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca²⁺, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. Methods: We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for in vivo studies. For in vitro studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. Trpm4 gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both in vitro and in vivo. Results: Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. Conclusions: TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.