Document Detail

Genetic and pharmacologic inhibition of the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+-dependent toxicity.
MedLine Citation:
PMID:  21354153     Owner:  NLM     Status:  MEDLINE    
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.
Min Seuk Kim; Kyu Pil Lee; Dongki Yang; Dong Min Shin; Joel Abramowitz; Shigeki Kiyonaka; Lutz Birnbaumer; Yasuo Mori; Shmuel Muallem
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2011-02-24
Journal Detail:
Title:  Gastroenterology     Volume:  140     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-06     Completed Date:  2011-08-09     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2107-15, 2115.e1-4     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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.
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MeSH Terms
Acute Disease
Calcium Channel Blockers / pharmacology*
Calcium Signaling / drug effects*
Disease Models, Animal
Epithelial Cells / drug effects*,  metabolism,  pathology,  secretion
Mice, Knockout
Pancreas / drug effects*,  metabolism,  pathology,  secretion
Pancreatitis / chemically induced,  drug therapy*,  genetics,  metabolism,  pathology
Pyrazoles / pharmacology*
Salivary Gland Diseases / drug therapy*,  genetics,  metabolism,  pathology
Salivary Glands / drug effects*,  metabolism,  pathology,  secretion
Severity of Illness Index
TRPC Cation Channels / antagonists & inhibitors*,  deficiency,  genetics
Time Factors
Grant Support
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Pyrazoles; 0/TRPC Cation Channels; 0/TRPC3 cation channel; 17650-98-5/Caerulein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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