| First Author | Kim MS | Year | 2009 |
| Journal | Gastroenterology | Volume | 137 |
| Issue | 4 | Pages | 1509-17 |
| PubMed ID | 19622358 | Mgi Jnum | J:302019 |
| Mgi Id | MGI:6507455 | Doi | 10.1053/j.gastro.2009.07.042 |
| Citation | Kim MS, et al. (2009) Deletion of TRPC3 in mice reduces store-operated Ca2+ influx and the severity of acute pancreatitis. Gastroenterology 137(4):1509-17 |
| abstractText | BACKGROUND & AIMS: Receptor-stimulated Ca(2+) influx is a critical component of the Ca(2+) signal and mediates all cellular functions regulated by Ca(2+). However, excessive Ca(2+) influx is highly toxic, resulting in cell death, which is the nodal point in all forms of pancreatitis. Ca(2+) 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 Ca(2+) signaling, exocytosis, intracellular trypsin activation, and pancreatitis. RESULTS: Deletion of TRPC3 reduced the receptor-stimulated and SOC-mediated Ca(2+) influx by about 50%, indicating that TRPC3 functions as an SOC in vivo. The reduced Ca(2+) influx in TRPC3(-/-) acini resulted in reduced frequency of the physiologic Ca(2+) oscillations and of the pathologic sustained increase in cytosolic Ca(2+) 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 Ca(2+) influx in the pathogenesis of acute pancreatitis and suggest that TRPC3 should be considered a target for prevention of pancreatic damage in acute pancreatitis. |
