| Genetic and pharmacologic inhibition of the Ca2+ influx channel TRPC3 protects secretory epithelia from Ca2+-dependent toxicity. | |
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MedLine Citation:
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PMID: 21354153 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2011-02-24 |
Journal Detail:
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Title: Gastroenterology Volume: 140 ISSN: 1528-0012 ISO Abbreviation: Gastroenterology Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-06 Completed Date: 2011-08-09 Revised Date: 2012-09-20 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 2107-15, 2115.e1-4 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Animals Caerulein Calcium Channel Blockers / pharmacology* Calcium Signaling / drug effects* Disease Models, Animal Epithelial Cells / drug effects*, metabolism, pathology, secretion Mice 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 | |
ID/Acronym/Agency:
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ZIA DE000735-01/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Calcium Channel Blockers; 0/Pyrazoles; 0/TRPC Cation Channels; 0/TRPC3 cation channel; 17650-98-5/Caerulein |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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