Details

Autor(en) / Beteiligte

• Kim, Min Seuk
• Lee, Kyu Pil
• Yang, Dongki
• Shin, Dong Min
• Abramowitz, Joel
• Kiyonaka, Shigeki
• Birnbaumer, Lutz
• Mori, Yasuo
• Muallem, Shmuel

Titel

Genetic and Pharmacologic Inhibition of the Ca2+ Influx Channel TRPC3 Protects Secretory Epithelia From Ca2+ -Dependent Toxicity

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2011-06, Vol.140 (7), p.2107-2115.e4

Ort / Verlag

United States

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.