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Genetic and pharmacologic inhibition of the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+-dependent toxicity

Authors
 Dongki Yang ; Dong Min Shin ; Kyu Pil Lee ; Min Seuk Kim ; Joel Abramowitz ; Shigeki Kiyonaka ; Lutz Birnbaumer ; Yasuo Mori ; Shmuel Muallem 
Citation
 Gastroenterology , Vol.140(7) : 2107~2115, 2115.e1-4, 2011 
Journal Title
 Gastroenterology 
ISSN
 0016-5085 
Issue Date
2011
Abstract
BACKGROUND & AIMS: Excessive Ca2+ influx mediates many cytotoxic processes, including those associated with autoimmune inflammatory diseases such as acute pancreatitis and Sjögren syndrome. Transient receptor potential (canonical) channel (TRPC) 3 is a major Ca2+ influx channel in pancreatic and salivary gland cells. We investigated whether genetic or pharmacologic inhibition of TRPC3 protects pancreas and salivary glands from Ca2+-dependent damage. METHODS: We developed a Ca2+-dependent model of cell damage for salivary gland acini. Acute pancreatitis was induced by injection of cerulein into wild-type and Trpc3-/- mice. Mice were also given the Trpc3-selective inhibitor pyrazole 3 (Pyr3). RESULTS: Salivary glands and pancreas of Trpc3-/- mice were protected from Ca2+-mediated cell toxicity. Analysis of Ca2+ signaling in wild-type and Trpc3-/- acini showed that Pyr3 is a highly specific inhibitor of Tprc3; it protected salivary glands and pancreas cells from Ca2+-mediated toxicity by inhibiting the Trpc3-mediated component of Ca2+ influx. CONCLUSIONS: TRPC3-mediated Ca2+ influx mediates damage to pancreas and salivary glands. Pharmacologic inhibition of TRPC3 with the highly selective TRPC3 inhibitor Pyr3 might be developed for treatment of patients with acute pancreatitis and Sjögren syndrome
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/93204
DOI
10.1053/j.gastro.2011.02.052.
Appears in Collections:
1. 연구논문 > 2. College of Dentistry > Dept. of Oral Biology
Yonsei Authors
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