title: Genetic and pharmacologic inhibition of the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+-dependent toxicity.
abstract: OBJECTIVE
  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.
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20814, USA.
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.forename: Kyu Pil
authors.initials: KP
authors.lastname: Lee
authors.forename: Dongki
authors.initials: D
authors.lastname: Yang
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Joel
authors.initials: J
authors.lastname: Abramowitz
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000208:Acute Disease; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002108:Ceruletide; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D012466:Salivary Gland Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012469:Salivary Glands / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D011720:Pyrazoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002108:Ceruletide